Supramaximal CCK-58 does not induce pancreatitis in the rat: role of pancreatic water secretion

Abstract

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.

Pancreas-specific aquaporin 12 null mice showed increased susceptibility to caerulein-induced acute pancreatitis

“…It has been reported that, in contrast to supramaximal CCK-8 or caerulein administration, supramaximal levels of CCK-58 do not cause pancreatitis. This is possibly attributable to the previously reported observation that supramaximal CCK-58 maintains pancreatic acinar water secretion, which is essential for exocytosis of activated zymogens (25). Clearly, therefore, a disruption to the water flow is one of the contributing factors in the onset of pancreatitis.…”

CCK-8 and CCK-58 differ in their effects on nocturnal solid meal pattern in undisturbed rats

“…CCK-58 induces a more sustained pancreatic protein secretion than CCK-8, as shown by the return to basal values at the end of the 3-h infusion period with CCK-8, whereas protein output remained significantly elevated compared with basal in CCK-58-treated rats (46,62). In addition, intravenous infusion of CCK-58 at 2 or 4 nmol·kg Ϫ1 ·h Ϫ1 for 6 h in a conscious rat model did not induce pancreatitis at a dose at which CCK-8 induced several parameters indicative of pancreatitis, including interstitial edema, inflammatory cell infiltration, intracellular vacuolization, increased pancreatic myeloperoxidase activity, and elevated serum amylase levels (61).…”

“…CCK-8 AND CCK-58: EFFECT ON FEEDING PATTERN (61). Sayegh and coworkers (33) have shown that effects of endogenous CCK on meal size and IMI are partly regulated by the CCK 1 receptor (55).…”

Pancreatic response of rats fed genetically modified soybean

“…There were regenerative changes on day 7 and day 14, with almost a complete recovery of zymogen granules by day 14. In contrast to supramaximal CCK-8 or caerulein, acute or prolonged supraphysiological levels of endogenous CCK-58, the only detectable endocrine form in the rat (Reeve et al, 2003), do not cause pancreatitis (Yamamoto et al, 2007). The response of rat pancreatic cells is limited and a down-regulation of the receptor CCK-A has been suggested as a protective mechanism (Ohlsson et al, 2000).…”