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

AbstractOBJECTIVES:
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.
AuthorsAlexey Aleshin, Yoshiki Sawa, Masamichi Ono, Toshihiro Funatsu, Shigeru Miyagawa, Hikaru Matsuda
JournalEuropean 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
PMID15519192 (Publication Type: Journal Article)
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
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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