Intraductal administration of an NK1 receptor antagonist attenuates the inflammatory response to retrograde infusion of radiological contrast in rats: implications for the pathogenesis and prevention of ERCP-induced pancreatitis.
BACKGROUND
The neurogenic inflammatory mediator, substance P (SP), has been implicated in the pathogenesis of acute secretagogue-induced pancreatitis. We hypothesized that it may also play an important role in the development of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). AIMS Our aim was to evaluate the effectiveness of CP-96345, a NK1 receptor antagonist, in diminishing post-ERCP pancreatitis in a rat model.


METHODS
The effects of CP-96345, when mixed with the contrast agent, were studied in a rat model of pancreatitis caused by retrograde contrast infusion. After 24 hours, histology, edema, and myeloperoxidase activity (MPO) of pancreas, plasma amylase, and NK1 receptor endocytosis in pancreatic acinar cells were evaluated.


RESULTS
Intraductal contrast infusion caused increases in plasma amylase, edema, histologic grade, and MPO of pancreas, and NK1 receptor internalization in pancreatic acinar cells. The addition of CP-96345 to the infusate significantly reduced pancreatic edema, MPO activity, and the histologic grade of pancreatitis accompanied by a decrease in NK1 receptor internalization.


CONCLUSIONS
When an NK1 receptor antagonist is delivered along with the contrast media there is significant reduction in the pancreatic inflammation caused by intraductal contrast infusion. These results provide some insight into the pathogenesis of ERCP induced pancreatitis as well as present novel pharmacological targets for its prevention.
He
Zhi-Jun
ZJ
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Enteric Neuromuscular Disorders and Pain Laboratory, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Winston
John H
JH
Yusuf
Tony E
TE
Micci
Maria-Adelaide
MA
Elfert
Asem
A
Xiao
Shu-Yuan
SY
Pasricha
Pankaj J
PJ
D000681:Amylases / Q000097:blood; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D002760:Cholangiopancreatography, Endoscopic Retrograde / Q000009:adverse effects*; D003287:Contrast Media; D004487:Edema / Q000473:pathology; D004705:Endocytosis / Q000187:drug effects; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001713:Biphenyl Compounds; D003287:Contrast Media; D064729:Neurokinin-1 Receptor Antagonists; D009195:Peroxidase; D000681:Amylases; C066892:CP 96345