Role of CCK and potential utility of CCK1 receptor antagonism in the treatment of pancreatitis induced by biliary tract obstruction.
OBJECTIVE
Cholecystokinin (CCK) stimulates the release of amylase and lipase from the normal pancreas. However, it is not clear to what extent this occurs in the early stages of pancreatitis induced by biliary tract obstruction in the rat and whether CCK initiates an inflammatory cascade in this condition.


METHODS
Selective CCK1 receptor antagonists, JNJ-17156516 ((S)-(3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid) and dexloxiglumide, were used to assess the response of plasma amylase and lipase to a CCK analogue, CCK8S, in normal rats and in rats with bile duct ligation.


RESULTS
Both antagonists suppressed CCK8S-induced elevation of plasma amylase activity in normal rats. JNJ-17156516 was more potent than dexloxiglumide (ED(50)=8.2 vs >30 micromol kg(-1) p.o.) and produced a longer lived inhibition (6 vs 2 h). Plasma amylase and lipase activity were elevated in parallel to CCK plasma concentrations after bile duct ligation and both activities were suppressed in a dose-dependent manner by JNJ-17156516 and dexloxiglumide. JNJ-17156516 was approximately 5- to 10-fold more potent than dexloxiglumide. Infusion of CCK8S to naïve rats to achieve levels similar to those observed after bile duct ligation (20 pM) increased plasma amylase activity and activated nuclear factor-kappaB in the pancreas. These effects were prevented by pretreatment with JNJ-17156516.


CONCLUSIONS
The elevation of plasma amylase and lipase activity in the early stages of obstruction-induced pancreatitis is largely driven by elevation of plasma CCK concentration and activation of CCK1 receptors. These data show that CCK is an initiating factor in acute pancreatitis in the rat.
Barrett
T D
TD
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, CA, USA. TBarret1@prdus.jnj.com
Yan
W
W
Freedman
J M
JM
Lagaud
G J
GJ
Breitenbucher
J G
JG
Shankley
N P
NP
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002766:Cholecystokinin / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D008026:Ligation; D008049:Lipase / Q000097:blood; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010195:Pancreatitis / Q000188:drug therapy* / Q000503:physiopathology; D010421:Pentanoic Acids / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology
C524698:3-(5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-2-m-tolylpropionic acid; C090019:8-sulfocholecystokinin octapeptide; D016328:NF-kappa B; D010421:Pentanoic Acids; D010666:Phenylpropionates; D011720:Pyrazoles; D043886:Receptor, Cholecystokinin A; C103490:dexloxiglumide; D002766:Cholecystokinin; D008049:Lipase; D000681:Amylases; D012844:Sincalide