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  • Title: Myocardial protective effect of FR167653; a novel cytokine inhibitor in ischemic-reperfused rat heart.
    Author: Aleshin A, Sawa Y, Ono M, Funatsu T, Miyagawa S, Matsuda H.
    Journal: Eur J Cardiothorac Surg; 2004 Nov; 26(5):974-80. PubMed ID: 15519192.
    Abstract:
    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 degrees C ischemia induced marked myocardial cytokine expression and activated p38MAPK. FR167653 administered before ischemia and during reperfusion significantly reduced ischemia-activated myocardial TNFalpha mRNA expression (190+/-97 vs. 4805+/-3017, P=0.024) as well as TNFalpha production (0 vs. 9.6+/-2.5 ng/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+/-21 mmHg (P=0.002)), max/min dP/dt (2812+/-328/-2283+/-216 vs. 1520+/-424/-1325+/-237 mmHg/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 TNFalpha 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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