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

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 30 min of 37 degreesC 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/dr (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 %) 1 h 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. (C) 2004 Elsevier B.V. All rights reserved.