Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production. Potential ultimate effector mechanism of preconditioning.
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.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Dinarello
C A
CA
Shames
B D
BD
Cleveland
J C
JC
Cain
B S
BS
Banerjee
A
A
Meng
X
X
Harken
A H
AH
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*
D014409:Tumor Necrosis Factor-alpha