Recently synthesized highly specific and potent bombesin receptor antagonists permit study of the role of endogenous bombesin-like peptides in the physiological regulation of pancreatic secretion. We now tested the action of three novel pseudononapeptide bombesin/gastrin releasing peptide (GRP) antagonists (RC-3095, RC-3100 and RC-3120) on amylase release in vitro from isolated rat pancreatic acini and on protein secretion in vivo in chronic pancreatic fistula rats. In isolated pancreatic acini, all three bombesin receptor antagonists inhibited the amylase secretion induced by bombesin by shifting to the right the amylase response to bombesin without altering the maximal response. These antagonists alos reduced concentration dependently the near-maximal amylase response to bombesin, the concentration required for 50% reduction (IC50) being about 10(-7) M for RC-3095 and RC-3100 and 10(-6) M for RC-3120. None of the bombesin/GRP antagonists used affected the amylase response to CCK, pentagastrin or urecholine. In conscious rats with a chronic pancreatic fistula, all three bombesin antagonists shifted to the right the pancreatic protein response to graded doses of bombesin without changing the maximal response. These antagonists inhibited the protein response to constant background stimulation with bombesin in a dose-dependent manner, the ID50 being about 20 nmol/kg per h for RC-3095 and RC-3100 and about 160 nmol/kg per h for RC-3120. None of the antagonists significantly affected basal pancreatic secretion or secretion induced by sham-feeding, ordinary feeding or the diversion of pancreatic juice from the duodenum. These results indicate that exogenous bombesin is a potent direct stimulant of pancreatic enzyme secretion.(ABSTRACT TRUNCATED AT 250 WORDS)