Supramaximal CCK-58 does not induce pancreatitis in the rat: role of pancreatic water secretion.
In contrast to supramaximal CCK-8 or caerulein, acute or prolonged supraphysiological levels of endogenous CCK-58 do not cause pancreatitis. Compared with CCK-8, CCK-58 is a much stronger stimulant of pancreatic chloride and water secretion, equivalent to maximally effective secretin, but with a chloride-to-bicarbonate ratio characteristic of acinar fluid. Because supraphysiological endogenous CCK does not cause pancreatitis and because coadministration of secretin ameliorated caerulein- or CCK-8-induced pancreatitis, coincident with restoring pancreatic water secretion, we hypothesized that supramaximal CCK-58 would not induce pancreatitis. Conscious rats were infused intravenously with 2 or 4 nmol x kg(-1) x h(-1) of CCK-8 or synthetic rat CCK-58 for 6 h, and pancreases were examined for morphological and biochemical indexes of acute pancreatitis. A second group was treated as above while monitoring pancreatic protein and water secretion. CCK-8 at 2 nmol x kg(-1) x h(-1) caused severe edematous pancreatitis as evidenced by morphological and biochemical criteria. CCK-58 at this dose had minimal or no effect on these indexes. CCK-58 at 4 nmol x kg(-1) x h(-1) increased some indexes of pancreatic damage but less than either the 2 or 4 nmol x kg(-1) x h(-1) dose of CCK-8. Pancreatic water and protein secretion were nearly or completely abolished within 3 h of onset of CCK-8 infusion, whereas water and protein secretion were maintained near basal levels in CCK-58-treated rats. We hypothesize that supramaximal CCK-58 does not induce pancreatitis because it maintains pancreatic acinar chloride and water secretion, which are essential for exocytosis of activated zymogens. We conclude that CCK-58 may be a valuable tool for investigating events that trigger pancreatitis.
Yamamoto
Mitsuyoshi
M
Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. m-yamamo@med.uoeh-u.ac.jp
Reeve
Joseph R
JR
Green
Gary M
GM
D000681:Amylases / Q000097:blood; D000818:Animals; D001834:Body Water / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D002766:Cholecystokinin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010189:Pancreatic Juice / Q000378:metabolism*; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012636:Secretory Rate; D012844:Sincalide / Q000633:toxicity*; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism
D002712:Chlorides; D015850:Interleukin-6; C038823:cholecystokinin 58; D014362:Trypsinogen; D002766:Cholecystokinin; D009195:Peroxidase; D000681:Amylases; D014357:Trypsin; D012844:Sincalide