Cardioplegic ischemia or reperfusion: which is a main trigger for tumor necrosis factor production?
BACKGROUND
Tumor necrosis factor alpha (TNF-alpha) is a key cytokine in the pathogenesis of ischemia-reperfusion injury (I/R) that also possesses negative inotropic and direct cardiotoxic effects. We investigated whether myocardial ischemia and/or reperfusion is the trigger for TNF-alpha synthesis and whether TNF-alpha release is time dependent.


METHODS
Isolated rat hearts undergoing 30 min of coronary perfusion with modified Krebs-Henseleit solution followed by cardioplegic arrest for 60 min of global cardioplegic normothermic ischemia (GCI) and 30 min of reperfusion using a modified Langendorff model. Myocardial TNF-mRNA expression and TNF-alpha protein levels in effluent from the coronary sinus were measured at baseline and then after 15, 30, and 60 min of GCI and after 10 and 30 min of reperfusion.


RESULTS
GCI induced myocardial TNF-alpha mRNA expression and elevation protein TNF-alpha levels in a time-dependent manner after 30 min of ischemia from 78+/-17 pg/ml to 915+/-287 pg/ml after 60 min (p<0.0015). Reperfusion did not cause time-dependent increase of TNF-alpha synthesis and release but was accompanied by progressive decrease of left ventricular (LV) function. There was a correlation between TNF-alpha protein levels and depression of LV function immediately after GCI but not with TNF-alpha protein levels at 30 min of reperfusion.


CONCLUSIONS
This study demonstrated that myocardial ischemia rather than reperfusion is the main trigger for time-dependent TNF-alpha synthesis. Depression of LV function during reperfusion correlated significantly only with TNF-alpha levels at the end of GCI.
Pevni
Dmitry
D
Department of Cardiothoracic Surgery, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Frolkis
Inna
I
Shapira
Itzhak
I
Schwartz
Doron
D
Schwartz
Idit
I
Chernichovski
Tamara
T
Nesher
Nahum
N
Uretzky
Gideon
G
D000704:Analysis of Variance; D000818:Animals; D002314:Cardioplegic Solutions / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D002314:Cardioplegic Solutions; D014409:Tumor Necrosis Factor-alpha