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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Authors | Alexey Aleshin, Yoshiki Sawa, Masamichi Ono, Toshihiro Funatsu, Shigeru Miyagawa, Hikaru Matsuda |
Journal | European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
(Eur J Cardiothorac Surg)
Vol. 26
Issue 5
Pg. 974-80
(Nov 2004)
ISSN: 1010-7940 [Print] Germany |
PMID | 15519192
(Publication Type: Journal Article)
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Chemical References |
- Cardiotonic Agents
- Cytokines
- Enzyme Inhibitors
- FR 167653
- Immunosuppressive Agents
- Pyrazoles
- Pyridines
- RNA, Messenger
- Tumor Necrosis Factor-alpha
- p38 Mitogen-Activated Protein Kinases
- Creatine Kinase
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Topics |
- Animals
- Apoptosis
(drug effects)
- Cardiotonic Agents
(therapeutic use)
- Creatine Kinase
(metabolism)
- Cytokines
(antagonists & inhibitors, biosynthesis)
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Gene Expression Regulation
(drug effects)
- Immunosuppressive Agents
(therapeutic use)
- Myocardial Reperfusion Injury
(immunology, pathology, prevention & control)
- Pyrazoles
(therapeutic use)
- Pyridines
(therapeutic use)
- RNA, Messenger
(genetics)
- Rats
- Rats, Inbred Lew
- Tumor Necrosis Factor-alpha
(biosynthesis, genetics)
- Ventricular Function, Left
(drug effects)
- p38 Mitogen-Activated Protein Kinases
(antagonists & inhibitors)
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