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Eur J Cardiothorac Surg 2004;26:974-980
© 2004 Elsevier Science NL

Myocardial protective effect of FR167653; a novel cytokine inhibitor in ischemic-reperfused rat heart

Division of Cardiovascular Surgery, First Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Received 22 January 2004; received in revised form 31 May 2004; accepted 16 June 2004.

^* Corresponding author. Tel.: +81-6-6879-3154; fax: +81-6-6879-3159. (E-mail: sawa{at}surg1.med.osaka-u.ac.jp).

Objectives: In this study, a newly synthesized cytokine inhibitor FR167653 was investigated using a rat heart ischemia-reperfusion model to prove its myocardial protective effect and its role in the inhibition of cytokine production in ischemic myocardium. Methods: Studies were performed with isolated, Langendorff-perfused Lewis rat hearts (n=80) which were either treated with FR167653 or untreated, as the control group, and subjected to ischemia-reperfusion. Results: Reperfusion followed by 30min of 37°C ischemia induced marked myocardial cytokine expression and activated p38MAPK. FR167653 administered before ischemia and during reperfusion significantly reduced ischemia-activated myocardial TNF mRNA expression (190±97 vs. 4805±3017, P=0.024) as well as TNF production (0 vs. 9.6±2.5ng/ml, P<0.05) and also inhibited p38 MAPK activation. Its administration improved recovery of cardiac contractile function during reperfusion: LVDP (130±18 vs. 82±21mmHg (P=0.002)), max/min dP/dt (2812±328/–2283±216 vs. 1520±424/–1325±237mmHg/s, P=0.003). CPK leakage was significantly reduced in FR167653 treated hearts versus untreated hearts (54±6 vs. 0.5±0.1, P<0.05) and reduction of coronary flow was improved (110±13 vs. 77±11%) 1h after beginning of reperfusion (P<0.05). Moreover, FR administration attenuated the number of TUNEL positive cardiomyocytes (3±1 vs. 9±2%). Conclusion: These data demonstrated positive inotropic and antiapoptotic effects of a newly synthesized compound (FR167653) of cytokine inhibitors and its inhibitory effect on myocardial TNF production and p38 MAPK activation in ischemic-reperfused rat heart. This suggested that cytokine inhibition is significant as a method for myocardial protection against ischemia-reperfusion injury.

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