title: Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production. Potential ultimate effector mechanism of preconditioning.
abstract: BACKGROUND
  Tumor necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion (I/R) injury, sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leukocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether ischemic preconditioning, which is mediated by adenosine, decreases postischemic myocardial TNF-alpha production.
  
  
  RESULTS
  Isolated rat hearts were crystalloid perfused with the Langendorff method and subjected to global, normothermic I/R (20/40 minutes), with or without prior transient ischemic preconditioning (5 minutes) or adenosine pretreatment. Postischemic cardiac TNF-alpha (ELISA) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Ischemic preconditioning or adenosine decreased myocardial TNF-alpha and improved postischemic functional recovery. Sequestration of myocardial TNF-alpha (TNF binding protein) during the I/R experiments similarly improved postischemic myocardial function.
  
  
  CONCLUSIONS
  This study constitutes the initial demonstration that in addition to its other beneficial effects, preconditioning decreases postischemic myocardial TNF-alpha, an autocrine contributor to postischemic myocardial dysfunction. Reduced myocardial TNF-alpha production may represent the distal effector mechanism of preconditioning.
authors.affiliation: Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Meldrum
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: B D
authors.initials: BD
authors.lastname: Shames
authors.forename: J C
authors.initials: JC
authors.lastname: Cleveland
authors.forename: B S
authors.initials: BS
authors.lastname: Cain
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.forename: A H
authors.initials: AH
authors.lastname: Harken
mesh_terms: D000818:Animals; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D014409:Tumor Necrosis Factor-alpha