In isolated mouse pancreatic acini, vasoactive intestinal polypeptide (VIP) and secretin potentiated amylase release stimulated by cholecystokinin (CCK). VIP (1-100 nM) or secretin (100-1000 nM) alone elicited a negligible secretory response, whereas in combination with CCK, these agents induced a significantly larger response. VIP increased maximal amylase release elicited by CCK without affecting the potency with which CCK stimulated secretion. The phosphodiesterase inhibitor, 3-isobutyl-1-methyl xanthine (IBMX), from 0.03-1.0 mM had effects on secretion similar to those of VIP. VIP, IBMX and 8-Br-cyclic AMP, all of which act through or mimic the action of cyclic AMP, potentiated the secretory response to maximal concentrations of CCK, carbamylcholine and the ionophore A23187, all of which act via intracellular calcium. In contrast to amylase release, stimulation of acinar glucose transport by CCK or carbamylcholine was not augmented by VIP, secretin, IBMX or 8-Br-cyclic AMP. The results indicate that for amylase release from mouse pancreas, secretagogues acting via cyclic AMP potentiate those acting via calcium. However, potentiation does not apply to all biological responses of the pancreatic acinus and each response must be studied individually.