Pharmacologic preconditioning of JTE-607, a novel cytokine inhibitor, attenuates ischemia-reperfusion injury in the myocardium.
BACKGROUND
Myocardial ischemia-reperfusion injury is a main cause of postoperative cardiac dysfunction, and a burst of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 8, plays a pivotal role. Recently, JTE-607 has been reported as a potent inhibitor of the multiple inflammatory cytokines in the endotoxin shock mouse model. In this study we proved the hypothesis that JTE-607 might attenuate myocardial ischemia-reperfusion injury in a rat model.


METHODS
The isolated rat hearts in the JTE-607 preconditioning group (J group, n = 8) or control group (C group, n = 8) were subjected to warm ischemia (37 degrees C) for 30 minutes, followed by 60 minutes of reperfusion with the Langendorff perfusion system.


RESULTS
Left ventricular developed pressure and maximum dp/dt after reperfusion were significantly improved in the J group than in the C group (P <.01). Creatine phosphokinase leakage is significantly lower in the J group (P <.05). Moreover, the tissue cytokine levels, such as tumor necrosis factor alpha, interleukin 6, and interleukin 8, in the myocardium were significantly lower in the J group than in the C group (P <.05).


CONCLUSIONS
These results suggested that the pharmacologic preconditioning of JTE-607 inhibits a burst of endogenous cytokines in the myocardium, resulting in the improvement of cardiac function after ischemia-reperfusion injury. Thus JTE-607 might be a novel therapeutic strategy for the protection of postoperative cardiac dysfunction in cardiac surgery.
Ryugo
Masahiro
M
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
Sawa
Yoshiki
Y
Ono
Masamichi
M
Miyamoto
Yuji
Y
Aleshin
Alexei N
AN
Matsuda
Hikaru
H
D000818:Animals; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000601:surgery; D015425:Myocardial Reperfusion / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011336:Probability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D015996:Survival Rate
D016207:Cytokines; C468268:JTE 607; D010879:Piperazines; D010649:Phenylalanine