KF24345, an adenosine uptake inhibitor, ameliorates the severity and mortality of lethal acute pancreatitis via endogenous adenosine in mice.
Adenosine protects against cellular damage and dysfunction under several adverse conditions including inflammation and ischemia. In this study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on experimental acute pancreatitis induced by choline-deficient and ethionine-supplemented diet in mice. KF24345, administered with the diet onset and every 24 h thereafter, prevented hyperamylasemia, acinar cell injury and serum tumor necrosis factor-alpha elevation and ultimately decreased mortality. Therapeutic treatment with KF24345, which started 32 h after the diet onset, also decreased mortality. The beneficial effect of KF24345 on mortality was abolished by the pretreatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), a selective adenosine A(2A) receptor antagonist. An intravenous injection of KF24345 at 48 h after the diet onset increased plasma adenosine concentrations in mice with acute pancreatitis. These results suggest that KF24345 shows anti-pancreatitis effects via endogenous adenosine and adenosine A(2A) receptors. The adenosine uptake inhibition could be a new therapeutic approach for acute pancreatitis.
Noji
Tohru
T
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Limited, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. tohru.noji@kyowa.co.jp
Nan-ya
Ken-ichiro
K
Mizutani
Mirai
M
Katagiri
Chikako
C
Sano
Jun-ichi
J
Takada
Chie
C
Nishikawa
Satoshi
S
Karasawa
Akira
A
Kusaka
Hideaki
H
D000208:Acute Disease; D000241:Adenosine / Q000037:antagonists & inhibitors* / Q000097:blood; D000681:Amylases / Q000097:blood; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D004032:Diet; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000097:blood; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009929:Organ Size; D010179:Pancreas / Q000187:drug effects; D010195:Pancreatitis / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D011744:Pyrimidinones / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C444645:3-(1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl)-1,6-dimethyl-2,4-(1H,3H)-quinazolinedione; D014179:Neurotransmitter Uptake Inhibitors; D011744:Pyrimidinones; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D000681:Amylases; D000241:Adenosine