The effects of neurotensin, a tridecapeptide localized mainly in the gut, on pancreatic secretion are controversial. It is not clear whether the effects are mediated by direct or indirect effects. The present study was done to determine the effect of threshold doses of neurotensin in vivo in the rat as well as in vitro to clarify whether the action is direct or indirect. For in vivo studies the pancreatic duct of rats was cannulated and threshold doses of neurotensin and CCK-8 alone or in combination were infused as an intravenous bolus and pancreatic juice collected at 10-min intervals for 1 hr. For in vitro studies dissociated lobules and acini were incubated for 1 hr with 10(-11) -10(-6) M neurotensin with or without 10(-9) M CCK-8 (maximally effective dose). Amylase secretion in the pancreatic juice or in the medium was determined. Neurotensin and CCK-8 at a dose of 50 pM/kg increased pancreatic protein secretion in vivo. Neurotensin in combination with CCK-8 did not potentiate protein secretion. In the pancreatic lobules and acini, neurotensin 10(-11) -10(-6) M alone or in combination with CCK-8 (10(-9) M) did not stimulate amylase secretion above the basal level or that stimulated with CCK-8. The combined data indicate that the effect of neurotensin is not mediated by a direct action on the pancreatic acinar cells.