Secretory responses of hypertrophied rat pancreas induced by repeated oral administrations of a synthetic protease inhibitor.

A dose of FOY-305 [N,N-dimethylcarbamoylmethyl-4-(4-guanidinobenzoyloxy)phenylacetate methanesulfonate; 100 mg/kg body weight] was administered orally once a day for 30 days to a group of rats (FOY group). To the control group of rats, 10 ml/kg body weight of distilled water (a solvent of FOY-305) was administered in the same way. The FOY-305 administration induced hypertrophy of the pancreas: the increase in wet weight of the pancreas was significantly higher than the increase in DNA content. The administration also induced hyperpyknia in the FOY group as shown by the increased concentration of constituents (amylase, trypsinogen, and chymotrypsinogen) in the pancreas. The secretory responses of the exocrine pancreas to stimulation with cholecystokinin (CCK) were examined in vivo. The secretory responses induced by lowered doses of CCK in the FOY group were slightly greater than those in the control group, but the differences were not statistically significant. On the other hand, the responses induced by higher doses of CCK were significantly greater than those in the control group. The secretory responses to stimulation with CCK or acetylcholine (ACh) were examined further in vitro using an isolated perfused pancreas. Protein output induced by lower doses of the secretagogues (146-730 pM CCK or 10 nM ACh) was similar in the control and the FOY groups, but the output induced by higher doses of the secretagogues (1,460 pM CCK or 30-100 nM ACh) in the FOY group was significantly larger than that in the control group. The present results provided evidence that the FOY-305-induced hypertrophy and hyperpyknia of the rat pancreas coincided with potentiation of secretory responses to higher doses of the secretagogues.