title: Aprotinin exerts differential and dose-dependent effects on myocardial contractility, oxidative stress, and cytokine release after ischemia-reperfusion.
abstract: BACKGROUND
  Cardiac surgery can result in left ventricular ischemia and reperfusion (I/R), the release of cytokines such as tumor necrosis factor, and oxidative stress with release of myeloperoxidase. Although aprotinin has been used in cardiac surgery, the likely multiple effects of this serine protease inhibitor limit clinical utility. This study tested the hypothesis that different aprotinin doses cause divergent effects on left ventricular contractility, cytokine release, and oxidative stress in the context of I/R.
  
  
  METHODS
  Left ventricular I/R (30 minutes I, 60 minutes R) was induced in mice, and left ventricular contractility (maximal end-systolic elastance) determined. Mice were randomly allocated to 2 x 10(4) kallikrein inhibitory units (KIU)/kg aprotinin (n = 11), 4 x 10(4) KIU/kg aprotinin (n = 10), and vehicle (saline, n = 10). Based upon a fluorogenic assay, aprotinin doses of 2 and 4 x 10(4) KIU/kg resulted in plasma concentrations similar to those of the half and full Hammersmith doses, respectively.
  
  
  RESULTS
  After I/R, maximal end-systolic elastance fell by more than 40% from baseline (p < 0.05), and this effect was attenuated by 2 x 10(4) KIU/kg but not 4 x 10(4) KIU/kg aprotinin. Tumor necrosis factor increased by more than 60% from control (p < 0.05) with I/R, but was reduced with 4 x 10(4) KIU/kg aprotinin. Myeloperoxidase increased with I/R, and was reduced to the greatest degree by 2 x 10(4) KIU/kg aprotinin.
  
  
  CONCLUSIONS
  Aprotinin influences left ventricular contractility, cytokine release, and oxidative stress, which are dose dependent. These results provide mechanistic evidence that multiple pathways are differentially affected by aprotinin in a context relevant to cardiac surgery.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Medical University of South Carolina, Charleston, South Carolina 29403, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McEvoy
authors.forename: Anna-Greta
authors.initials: AG
authors.lastname: Taylor
authors.forename: Juozas A
authors.initials: JA
authors.lastname: Zavadzkas
authors.forename: Ira M
authors.initials: IM
authors.lastname: Mains
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Ford
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: Laura B
authors.initials: LB
authors.lastname: Jeffords
authors.forename: Christy U
authors.initials: CU
authors.lastname: Beck
authors.forename: Scott T
authors.initials: ST
authors.lastname: Reeves
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D007611:Aprotinin / Q000008:administration & dosage*; D006348:Cardiac Surgical Procedures; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004548:Elasticity; D007091:Image Processing, Computer-Assisted; D015850:Interleukin-6 / Q000032:analysis; D051379:Mice; D008815:Mice, Inbred Strains; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000032:analysis; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D015850:Interleukin-6; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007611:Aprotinin; D009195:Peroxidase