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
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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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