Inhibitory effects of edaravone on the production of tumor necrosis factor-alpha in the isolated heart undergoing ischemia and reperfusion.
We evaluated the effects of edaravone, a hydroxyl radical scavenging agent, on the production of tumor necrosis factor-alpha (TNF-alpha) in myocardium, and the release of TNF-alpha and P-selectin from myocardium after ischemia-reperfusion injury in isolated Langendorff-perfused rat hearts. Cardiodynamic function at stable points during perfusion and 5, 15, 30, and 60 min after the initiation of reperfusion was evaluated by left ventricular developed pressure, rate of increase in left ventricular pressure and rate of decrease in ventricular pressure, coronary flow, and heart rate. At 60 min after the initiation of reperfusion, myocardial infarct size was estimated microscopically using triphenyltetrazolium chloride staining, and expression of TNF-alpha in myocardium was detected by Western blot and immunohistochemistry. At the same time points as the measurement of cardiodynamic function, TNF-alpha and the soluble form of P-selectin in coronary effluent were measured by enzyme immunoassay. At all time points during reperfusion, edaravone markedly improved cardiodynamic function and reduced myocardial infarct size in comparison to the control. In myocardium in the control, TNF-alpha was detected in the endothelial cells and other cells bearing some resemblance to interstitial cells and monocyte cells. Edaravone suppressed this cytokine expression in the corresponding sites. P-selectin as well as TNF-alpha was found in the coronary effluent of the control, and edaravone significantly decreased soluble P-selectin levels in comparison to the control (P < 0.01). Edaravone might have protective effects on cardiac function through reduction of infarct size via decrease of production of TNF-alpha in myocardium induced by ischemia-reperfusion injury and through reduction of the release of adhesion molecules such as P-selectin from vascular endothelial cells.
Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Shunji
S
Onimaru
Kazuo
K
Nakamura
Hiroko
H
Kariyazono
Ryuji
R
Ikeda
Takayuki
T
Ueno
Yoshihiro
Y
Fukumoto
Akira
A
Yabuki
Ryuzo
R
Sakata
Katsushi
K
Yamada
D000704:Analysis of Variance; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007124:Immunoenzyme Techniques; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D019007:P-Selectin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
D016166:Free Radical Scavengers; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha; D000077553:Edaravone; D000983:Antipyrine