Adenosine uptake inhibition ameliorates cerulein-induced acute pancreatitis in mice.
OBJECTIVE
Adenosine shows protective effects against cellular damage and dysfunction under several adverse conditions such as inflammation and ischemia. In the current study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1,3 )-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on cerulein-induced acute pancreatitis in mice to investigate whether inhibition of adenosine uptake could ameliorate the severity of acute pancreatitis.


METHODS
Acute pancreatitis was induced in mice with six intraperitoneal injections of cerulein (50 microg/kg each) at hourly intervals.


RESULTS
The cerulein injection increased activities of serum amylase and lipase and caused pathologic changes such as interstitial edema, polymorphonuclear cell infiltration, and acinar cell necrosis in the pancreas. KF24345 (10 mg/kg p.o.) ameliorated all these changes observed in mice with acute pancreatitis, and the suppressing effect of KF24345 on the elevation in serum amylase activity was abolished by the treatment with 8-(p-sulfophenyl)theophylline, an adenosine receptor antagonist. In addition, 2-(aminocarbonyl)- -(4-amino-2,6-dichlorophenyl)-4-[5,5-bis-(4-fluorophenyl)pentyl]-1-piperazineacetamide (R75231) and dipyridamole, other adenosine uptake inhibitors, also decreased the elevated serum amylase activity.


CONCLUSIONS
These are the first demonstrations that the adenosine uptake inhibitors ameliorate cerulein-induced acute pancreatitis in mice, and these data suggest that adenosine uptake inhibition could ameliorate the severity of acute pancreatitis in vivo.
Noji
Tohru
T
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan. tohru.noji@kyowa.co.jp
Nan-ya
Ken-ichiro
K
Katagiri
Chikako
C
Mizutani
Mirai
M
Sano
Jun-ichi
J
Nishikawa
Satoshi
S
Karasawa
Akira
A
Kusaka
Hideaki
H
D000208:Acute Disease; D000241:Adenosine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000681:Amylases / Q000097:blood; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002108:Ceruletide; D004176:Dipyridamole / Q000494:pharmacology; D005260:Female; D008049:Lipase / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D011744:Pyrimidinones / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011799:Quinazolines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
C444645:3-(1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl)-1,6-dimethyl-2,4-(1H,3H)-quinazolinedione; D010879:Piperazines; D011744:Pyrimidinones; D011799:Quinazolines; C072040:draflazine; D004176:Dipyridamole; C031433:8-(4-sulfophenyl)theophylline; D002108:Ceruletide; D013806:Theophylline; D008049:Lipase; D000681:Amylases; D000241:Adenosine