We examined the effects of bombesin on rat pancreatic digestive enzyme gene expression using cloned complementary DNA probes for amylase, trypsinogen I, chymotrypsinogen B, and lysophospholipase. Rats were injected sc three times daily with 5 nmol/kg body wt bombesin. Pancreata were investigated after 6, 12, 24, 48, and 120 h of hormone treatment. Bombesin administration resulted in a time-dependent increase of pancreatic weight, as well as DNA and protein concentration. Cellular hypertrophy became evident after 48 h, and pancreatic hyperplasia occurred after 5 days of hormone treatment. Bombesin administration resulted in a time-dependent parallel decrease of amylase and lysophospholipase messenger RNA (mRNA) concentrations with maximal inhibition occurring after 120 h of bombesin treatment (13 +/- 1% and 14 +/- 3% of control, respectively, P less than 0.05, n = 6). In contrast, chymotrypsin and trypsin mRNA levels remained unaltered after bombesin treatment for up to 5 days. Amylase and chymotrypsin enzyme levels did not correlate with their respective mRNA concentrations. Both decreased to approximately 50% of control after 12 h and increased to 126 +/- 38% of control and 388 +/- 109% of control (P less than 0.05, n = 6), respectively, after 5 days of bombesin treatment. To test whether the bombesin regulation was mediated by the release of cholecystokinin (CCK), the specific CCK receptor antagonist L-364,718 (1 mg/kg body wt) was injected ip either alone, or 15 min before each bombesin injection for 5 days. Although the antagonist alone significantly reduced the mRNA concentrations for trypsin, chymotrypsin, and lysophospholipase to approximately 50%, it did not block the effects of bombesin on pancreatic digestive enzyme levels. These data therefore indicate that bombesin regulates pancreatic digestive enzyme mRNA and protein concentrations in a nonparallel manner; furthermore, CCK is not involved in mediating the bombesin effects on pancreatic gene expression.