Activation of adenosine A2a receptor pathway reduces leukocyte infiltration but enhances edema formation in rat caerulein pancreatitis.
BACKGROUND
Adenosine plays important roles in a variety of pathophysiologic conditions through receptor-mediated mechanisms. Recent studies have shown that adenosine exerts potent anti-inflammatory properties that are chiefly brought about through the occupancy of the A2a receptor.


OBJECTIVE
To examine the effect of A2a receptor stimulation or inhibition on the pathologic findings during acute pancreatitis.


METHODS
Rats were randomized into three groups and received a selective A2a receptor agonist CGS-21680 (CGS), a selective A2a antagonist 3,7-dimethyl-1-[2-propynyl]-xanthine (DMPX), or saline. Thirty minutes after the injection, acute pancreatitis was produced in the rats by seven intraperitoneal injections of caerulein. The severity of acute pancreatitis was evaluated by serum amylase activity, pancreas myeloperoxidase (MPO) activity, Evans blue extravasation, and pathologic changes of the pancreas. In addition, we investigated the effects of CGS on the pathologic findings of caerulein pancreatitis induced in neutrophil-depleted rats.


RESULTS
Administration of caerulein produced hyperamylasemia and morphologic changes of the pancreas including interstitial edema, acinar cell vacuolization, and infiltration of inflammatory cells. In CGS-treated rats, the pancreatic edema and the Evans blue extravasation were aggravated significantly compared with those of saline-treated rats, whereas leukocyte infiltration and MPO activity of the pancreas were decreased. In contrast to CGS, administration of DMPX ameliorated the pancreatic edema and Evans blue extravasation. Treatment with CGS accelerated the pancreatic edema in pancreatitis even after the depletion of neutrophils.


CONCLUSIONS
The activation of adenosine A2a receptors modulates the pathology of acute pancreatitis through at least two diverse properties. One is an anti-inflammatory effect involving neutrophils, and the other is a propagating effect for pancreatic edema formation. The actions of the A2a receptor pathways are unique, and they may have an important role in the progression of acute pancreatitis.
Satoh
Akihiko
A
Department of Gastroenterology, Division of Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. asato@int3.med.tohoku.ac.jp
Satoh
Kennichi
K
Masamune
Atsushi
A
Yamagiwa
Tetsuya
T
Shimosegawa
Tooru
T
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D002108:Ceruletide; D004487:Edema / Q000139:chemically induced; D007962:Leukocytes / Q000276:immunology; D008297:Male; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013805:Theobromine / Q000031:analogs & derivatives* / Q000494:pharmacology
D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C057837:3,7-dimethyl-1-propargylxanthine; D002108:Ceruletide; D000681:Amylases; D000241:Adenosine; D013805:Theobromine