To examine whether
adenosine reduces
ischemia/reperfusion (I/R)-induced liver injury by inhibiting leukocyte activation via A(2) receptor (A(2)R) stimulation, we investigated the effects of
adenosine and selective A(2A) receptor (A(2A)R) 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 Ca(2+) 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)-alpha production by monocytes stimulated with
endotoxin by about 50%. Although
ZM241385, a selective A(2A)R antagonist, significantly enhanced the increase in
neutrophil elastase release and intracellular Ca(2+) concentrations in neutrophils stimulated with fMLP, this agent did not affect the
endotoxin-induced
TNF-alpha 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-alpha,
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 A(2A)R stimulation.