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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Adenosine and Selective A2A Receptor Agonists Reduce Ischemia/Reperfusion Injury of Rat Liver Mainly by Inhibiting Leukocyte Activation

Naoaki Harada, Kenji Okajima, Kazunori Murakami, Sadaharu Usune, Chiemi Sato, Koichi Ohshima and Takeshi Katsuragi
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 1034-1042;
Naoaki Harada
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Kenji Okajima
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Kazunori Murakami
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Sadaharu Usune
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Chiemi Sato
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Koichi Ohshima
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Takeshi Katsuragi
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Abstract

To examine whether adenosine reduces ischemia/reperfusion (I/R)-induced liver injury by inhibiting leukocyte activation via A2receptor (A2R) stimulation, we investigated the effects of adenosine and selective A2A receptor (A2AR) agonists (YT-146 and CGS21680C) on I/R-induced liver injury in rats. Adenosine, YT-146, and CGS21680C, in the concentration of 10−7 to 10−5 M, significantly inhibited neutrophil elastase release by about 30 to 40% and increased intracellular Ca2+ concentrations in isolated neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro. Adenosine, YT-146, and CGS21680C, in the concentration of 10−7 to 10−5 M, significantly inhibited tumor necrosis factor (TNF)-α production by monocytes stimulated with endotoxin by about 50%. Although ZM241385, a selective A2AR antagonist, significantly enhanced the increase in neutrophil elastase release and intracellular Ca2+concentrations in neutrophils stimulated with fMLP, this agent did not affect the endotoxin-induced TNF-α production by monocytes. Rats were subjected to liver ischemia for 60 min. Serum levels of transaminases increased after hepatic I/R, peaking at 12 h after reperfusion. The i.v. infusion of adenosine (1 and 10 mg/kg/h), YT-146 (0.1 and 1 mg/kg/h), and CGS21680C (0.1 and 1 mg/kg/h) significantly inhibited the I/R-induced increase in serum transaminase levels 12 h after reperfusion. The I/R-induced decrease in hepatic tissue blood flow was significantly prevented by adenosine and YT-146. Hepatic levels of TNF-α, cytokine-induced neutrophil chemoattractant (equivalent to human interleukin-8), and myeloperoxidase were significantly increased after I/R. These increases were significantly inhibited by the administration of adenosine, YT-146, and CGS21680C. Although the histological neutrophil accumulation in the liver was significantly increased after I/R as evaluated by the naphthol AS-D chloroacetate technique, the administration of adenosine, YT-146, and CGS21680C significantly inhibited this increase. These findings suggest that adenosine reduces I/R-induced liver injury both by inhibiting the synthesis of inflammatory mediators and by inhibiting neutrophil degranulation directly, probably through A2AR stimulation.

Footnotes

  • Send reprint requests to: Naoaki Harada, M.D., Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan. E-mail:naoha{at}Msat.fukuoka-u.ac.jp

  • Abbreviations:
    TNF-α
    tumor necrosis factor-α
    I/R
    ischemia/reperfusion
    fMLP
    formyl-methionyl-leucyl-phenylalanine
    LPS
    lipopolysaccharide
    CINC
    cytokine-induced neutrophil chemoattractant
    MPO
    myeloperoxidase
    ALT
    alanine aminotransferase
    AST
    aspartate aminotransferase
    [Ca2+]i
    intracellular Ca2+ concentration
    PMN
    polymorphonuclear leukocyte
    ELISA
    enzyme-linked immunosorbent assay
    IL
    interleukin
    DMSO
    dimethyl sulfoxide
    • Received September 17, 1999.
    • Accepted May 15, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Adenosine and Selective A2A Receptor Agonists Reduce Ischemia/Reperfusion Injury of Rat Liver Mainly by Inhibiting Leukocyte Activation

Naoaki Harada, Kenji Okajima, Kazunori Murakami, Sadaharu Usune, Chiemi Sato, Koichi Ohshima and Takeshi Katsuragi
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1034-1042;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Adenosine and Selective A2A Receptor Agonists Reduce Ischemia/Reperfusion Injury of Rat Liver Mainly by Inhibiting Leukocyte Activation

Naoaki Harada, Kenji Okajima, Kazunori Murakami, Sadaharu Usune, Chiemi Sato, Koichi Ohshima and Takeshi Katsuragi
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1034-1042;
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