Adenosine and selective A(2A) receptor agonists reduce ischemia/reperfusion injury of rat liver mainly by inhibiting leukocyte activation

Citation
N. Harada et al., Adenosine and selective A(2A) receptor agonists reduce ischemia/reperfusion injury of rat liver mainly by inhibiting leukocyte activation, J PHARM EXP, 294(3), 2000, pp. 1034-1042
Citations number
49
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
294
Issue
3
Year of publication
2000
Pages
1034 - 1042
Database
ISI
SICI code
0022-3565(200009)294:3<1034:AASARA>2.0.ZU;2-2
Abstract
To examine whether adenosine reduces ischemia/reperfusion (I/R)-induced liv er injury by inhibiting leukocyte activation via A(2) receptor (A(2)R) stim ulation, we investigated the effects of adenosine and selective A(2A) recep tor (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 t o 40% and increased intracellular Ca2+ concentrations in isolated neutrophi ls stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro. A denosine, YT-146, and CGS21680C, in the concentration of 10(-7) to 10(-5) M , significantly inhibited tumor necrosis factor (TNF)-alpha production by m onocytes stimulated with endotoxin by about 50%. Although ZM241385, a selec tive A(2A)R antagonist, significantly enhanced the increase in neutrophil e lastase release and intracellular Ca2+ concentrations in neutrophils stimul ated with FMLP, this agent did not affect the endotoxin-induced TNF-alpha p roduction by monocytes. Rats were subjected to liver ischemia for 60 min. S erum levels of transaminases increased after hepatic I/R, peaking at 12 h a fter 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 inhib ited the VR-induced increase in serum transaminase levels 12 h after reperf usion. The I/R-induced decrease in hepatic tissue blood flow was significan tly prevented by adenosine and YT-146. Hepatic levels of TNF-alpha, cytokin e-induced neutrophil chemoattractant (equivalent to human interleukin-8), a nd myeloperoxidase were significantly increased after I/R. These increases were significantly inhibited by the administration of adenosine, YT-146, an d CGS21680C. Although the histological neutrophil accumulation in the liver was significantly increased after I/R as evaluated by the naphthol AS-D ch loroacetate technique, the administration of adenosine, YT-146, and CGS2168 0C significantly inhibited this increase. These findings suggest that adeno sine reduces I/R-induced liver injury both by inhibiting the synthesis of i nflammatory mediators and by inhibiting neutrophil degranulation directly, probably through A(2A)R stimulation.