The effect of antagonism of adenosine A1 receptor against ischemia and reperfusion injury of the liver.
BACKGROUND
Adenosine is known to exert protective roles in hepatic ischemia and reperfusion injury, while all adenosine receptors do not play the cytoprotective roles. We have tested our hypothesis that blockage of adenosine binding to A(1) receptor by its antagonist, KW3902 [8-(noradamantan-3-yl)-1,3-dipropylxanthine] attenuates hepatic ischemia-reperfusion injury.


METHODS
Adult female beagle dogs underwent a 2 h total hepatic vascular exclusion (THVE) with a venovenous bypass. Nontreated animals that underwent THVE with a venovenous bypass alone were used as the control (Group CT, n=6). KW3902 was given to the animals by continuous intraportal infusion for 60 min before ischemia at a dose of 1 microg/kg/min (Group KW, n=6). Two wk survival, hemodynamics, hepatic tissue blood flow (HTBF), liver function, energy metabolism, cAMP concentration, and histopathological findings were studied.


RESULTS
Two wk animal survival was significantly improved in group KW compared with that in group CT (group CT: 16.7% versus group KW: 83.3%). HTBF, liver function, and hepatic adenine nucleotide concentration were remarkably better in group KW than group CT. In addition, cAMP concentration in group KW was maintained significantly higher than group CT. Histopathological examination revealed preservation of hepatic architecture and suppression of neutrophil infiltration into hepatic tissue in group KW.


CONCLUSIONS
Administration of adenosine A(1) receptor antagonist before ischemia attenuates hepatic ischemia-reperfusion injury. To elicit the beneficial effect of adenosine against ischemia and reperfusion injury of the liver, it is important to oppose adenosine A1 receptor activation.
Magata
Shinichiro
S
Department of Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. smagatajp@yahoo.co.jp
Taniguchi
Masahiko
M
Suzuki
Tomomi
T
Shimamura
Tsuyoshi
T
Fukai
Moto
M
Furukawa
Hiroyuki
H
Fujita
Miri
M
Todo
Satoru
S
D058916:Adenosine A1 Receptor Antagonists; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D000242:Cyclic AMP / Q000032:analysis / Q000096:biosynthesis; D004285:Dogs; D004734:Energy Metabolism; D005260:Female; D006339:Heart Rate; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008102:Liver Circulation; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D014970:Xanthines / Q000627:therapeutic use*
D058916:Adenosine A1 Receptor Antagonists; D014970:Xanthines; C073525:rolofylline; D000242:Cyclic AMP; D000410:Alanine Transaminase