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Conclusion: Our results suggest that the cholecystokinin (CCK) receptor antagonist L-364,718 has a protective effect on taurocholate-induced pancreatitis, and thus, it is inferred that CCK may have a significant pathophysiological role in the early phase of pancreatitis., Background: Conflicting results have been obtained from studies designed to determine the role of CCK in the initial stages of pancreatitis., Methods: We evaluated the protective effect of the CCK receptor antagonist L-364,718 (devazepide) and of the trypsin inhibitor camostat, on taurocholate-induced pancreatitis in rats. L-364,718 (1 mg/kg) or camostat (200 mg/kg) was administered intragastrically 30 min before the induction of pancreatitis., Results: Infusion of sodium taurocholate (50 mg/kg) into the pancreaticobiliary duct caused severe pancreatitis with marked hyperamylasemia and reduction of tissue enzyme content at 12 h postinfusion. Pretreatment with L-364,718, but not with camostat, caused significant improvement in signs of experimental pancreatitis based on tissue enzyme content and morphology. Compared with untreated pancreatitis, there was relatively well-preserved lobular architecture, less edema, less infiltration of inflammatory cells, and more zymogen granules after L-364,718 pretreatment. Moreover, the reduction of enzyme content owing to pancreatitis was ameliorated by L-364,718 pretreatment.

In the present study, we examined stimulus-secretion coupling in pancreatic acini prepared from rats given synthetic protease inhibitor camostate at a dose of 200 mg/kg body wt by an orogastric tube once a day for 10 d. Camostate treatment significantly increased pancreatic weight, protein, DNA, and enzyme contents. In acini prepared from the camostate-treated rats, responsiveness to both CCK-8 and carbamylcholine was greatly decreased with no shift in the dose-response curves compared to control acini prepared from saline-treated rats. There were no major changes in the affinity for both high- and low-affinity sites of CCK receptors, but there was a significant reduction in the capacity of low-affinity site based on acinar protein. Responsiveness to secretin in the camostate-treated rat acini was also significantly reduced compared with that in the controls. However, amylase release from the camostate-treated rat acini in response to an increase in intracellular calcium levels induced by the calcium ionophores A23187 or to an increase in intracellular cyclic 3',5'-monophosphate (cyclic AMP) levels caused by 8 bromo cyclic AMP was not significantly different from the control rat acini, suggesting that both Ca(2+)-dependent tyrosine kinase and nucleotide-activated kinases are not impaired. On the other hand, the responsiveness to phorbol ester TPA, which stimulates amylase secretion via a calcium-independent cascade by activating protein kinase C directly, was reduced in the camostate-treated rat acini compared with the controls. These results suggest the possibilities that the reduced amylase secretion in the camostate-treated rats is owing to alterations in both the transmembrane signal transduction and the phosphorylation of regulatory proteins by the Ca(2+)-independent, protein kinase C-dependent mechanisms.

The intraduodenal application of a potent protease inhibitor (camostate, 600 mg) causes a significant increase in basal pancreatic secretion in the manner of a negative-feedback mechanism. The integrated protein secretion during the entire study period was 9.9 +/- 1.8 g in 120 min. The iv application of anti-GRP immunoglobulin caused a significant reduction to 5.0 +/- g in 120 min. No significant changes in the plasma concentrations of GRP and CCK were detectable. The increased secretion occurring after the administration of the protease inhibitor could be mediated by neural GRP-dependent mechanisms. These may also be relevant for CCK-dependent factors, which are only briefly mentioned.

The effects of ion-transport blockers on CCK-8-induced protein output and concomitant fluid secretion were compared in isolated, perfused normal and hypertrophied rat pancreata. In the normal pancreas, perfusion with ouabain (1 mM), amiloride (1 mM), furosemide (1 mM), or SITS (0.1 mM) caused corresponding inhibition of both fluid and protein secretion that was induced by 100 pM CCK-8. Hypertrophy of the pancreas was produced by oral administration of a synthetic protease inhibitor (FOY-305) once a day for 3 wk. In the hypertrophied pancreas, perfusion with ouabain (0.1 or 1 mM) or amiloride (0.1 mM or 1 mM) decreased CCK-8-induced fluid secretion without changing CCK-8-induced protein output. Perfusion with furosemide (1 mM) inhibited both fluid and protein secretion induced by CCK-8, but the amount of inhibition of fluid secretion was much greater than that of protein secretion. Perfusion with SITS (0.1 mM) significantly decreased CCK-8-induced fluid secretion but not protein secretion. These results indicate that in contrast to a normal rat pancreas, the coupling of fluid and protein secretion induced by CCK-8 can be disrupted by experimental procedures that induce hypertrophy in the rat pancreas.

The hepatic metabolism and biliary and pancreatic excretion of the serine protease inhibitor camostat mesilate and its metabolites FOY-251 and GBA were studied in rats in vivo and in in sutu liver-perfusion experiments. After oral feeding (100 mg/kg) and iv infusion (5 mg/kg.h) of camostat mesilate, the original compound and both metabolites appeared in bile, but could not be detected in pancreatic juice. In plasma, only FOY-251 and GBA were detected. In the perfused rat liver, camostat mesilate (10 microM) was eliminated by 33.8% and its molar rate of degradation to FOY-251 was 25.1%. During the study period about 0.1% of camostat mesilate and FOY-251 appeared in bile. The liver perfusion of FOY-251 or GBA revealed very low hepatic extraction rates of 10.3 and 2.4%, respectively. In conclusion, the low hepatic extraction rate of camostat mesilate and its metabolites leads to high concentrations of the active metabolite FOY-251 in plasma. Camostat mesilate and its metabolites are effectively excreted into bile, but not in rat pancreatic juice.

A single dose of the synthetic proteinase inhibitor, Camostat (FOY-305; 100 mg/kg), was administered orally to rats. Pancreata were isolated and then perfused to examine the change in the level of resting fluid secretion. As early as 6 h after administration of the single dose of Camostat, the resting fluid secretion was significantly elevated. Twelve hours after administration, resting fluid secretion was maximally elevated, whereas contents of trypsinogen, chymotrypsinogen, and amylase per DNA in the pancreas were significantly decreased. After 12 h, the level of resting fluid secretion gradually decreased to the control resting level in contrast to significant increases in contents of the pancreatic enzyme and zymogens, and wet weight in acinar cells. We further examined the mechanism mediating the elevated resting fluid secretion. Our results are compatible with the view that the elevation of resting fluid secretion may be maintained by spontaneous activation of ion transporters: an ouabain-sensitive Na-K ATPase, an amiloride-sensitive Na-H antiporter, and a unique Cl transporter that is insensitive to furosemide, bumetanide, SITS, and DNDS.

This article suggests that for the concept of feedback regulation of the pancreas the application of animal data to humans has obvious limitations. The introduction of the synthetic protease inhibitor camostate (FOY 305) offered the possibility of designing studies in animals and man using the same compound as tool thus allowing reliable comparisons between the different experiments. These experiments revealed that cholecystokinin (CCK) has a dominant role in rats but it has no proven significance for feedback regulation in humans. The existence of such species differences should be kept in mind in studies dealing with pancreatic secretion, growth, pancreatitis, cancer, or related questions.