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Vol. 294, Issue 3, 1034-1042, September 2000
Department of Pharmacology (N.H., T.K.), Research Laboratory of
Biodynamics (S.U., C.S.), and Department of Pathology (K.Oh.), School
of Medicine, Fukuoka University, Fukuoka, Japan; and Department of
Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto,
Japan (K.Ok., K.M.)
To examine whether adenosine reduces ischemia/reperfusion (I/R)-induced
liver injury by inhibiting leukocyte activation via A2
receptor (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 105 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
107 to 105 M, significantly inhibited
tumor necrosis factor (TNF)-
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- 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-, 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.
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