title: Aprotinin modifies left ventricular contractility and cytokine release after ischemia-reperfusion in a dose-dependent manner in a murine model.
abstract: BACKGROUND
  Periods of ischemia-reperfusion (I/R) during cardiac surgery are associated with transient left ventricular (LV) dysfunction and an inflammatory response. In this study, we examined the potential dose-dependent effects of aprotinin (APRO) on LV contractility and cytokine release in the setting of I/R.
  
  
  METHODS
  An index of LV contractility, LV maximal elastance (E(max)), was measured at baseline, 30 min of ischemia, and 60 min of reperfusion by microtransducer volumetry. Mice were randomized as follows: (a) APRO 20,000 kallikrein-inhibiting units (KIU)/kg (n = 11); (b) APRO 4 x 10(4) KIU/kg (n = 10); (c) APRO 8 x 10(4) KIU/kg (n = 10); and (d) vehicle (saline; n = 10). APRO doses were calculated to reflect half, full, and twice the clinical Hammersmith dosing schedule. After I/R, plasma was collected for cytokine measurements.
  
  
  RESULTS
  After I/R, E(max) decreased from the baseline value by more than 40% in the vehicle group as well as in the APRO 4 x 10(4) KIU/kg and APRO 8 x 10(4) KIU/kg groups (P < 0.05). However, E(max) returned to near baseline values in the APRO 2 x 10(4) KIU/kg group. Tumor necrosis factor (TNF) increased 10-fold after I/R, but it was reduced with higher APRO doses.
  
  
  CONCLUSIONS
  This study demonstrated that a low dose of APRO provided protective effects on LV contractility, whereas higher doses suppressed TNF release. These unique findings suggest that there are distinct and independent mechanisms of action of APRO in the context of I/R.
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: Michel J
authors.initials: MJ
authors.lastname: Sabbagh
authors.forename: Anna Greta
authors.initials: AG
authors.lastname: Taylor
authors.forename: Juozas A
authors.initials: JA
authors.lastname: Zavadzkas
authors.forename: Christine N
authors.initials: CN
authors.lastname: Koval
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Ford
authors.forename: Julie E
authors.initials: JE
authors.lastname: McLean
authors.forename: Scott T
authors.initials: ST
authors.lastname: Reeves
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D007611:Aprotinin / Q000097:blood / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004548:Elasticity; D006439:Hemodynamics / Q000502:physiology; D006490:Hemostatics / Q000097:blood / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D016207:Cytokines; D006490:Hemostatics; D014409:Tumor Necrosis Factor-alpha; D007611:Aprotinin