In pancreatic acinar cells the effects of vasoactive intestinal polypeptide (VIP) and dibutyryl cyclic AMP (dbcAMP) alone and during stimulation with acetylcholine (ACh) or internally applied inositol trisphosphate (InsP3) were investigated utilizing the patch-clamp whole-cell current recording configuration to assess changes in cytoplasmic Ca2+ concentration by measurement of Ca2+ dependent Cl- current. VIP (1 nM) and dbcAMP (0.5 mM) each evoked repetitive pulses of Ca(2+)-dependent Cl- current. A high VIP concentration (100 nM) acutely and reversibly inhibited the responses evoked by 1 nM VIP and also acutely inhibited ACh-evoked responses. DbcAMP (2 mM) also reversibly inhibited the ACh-evoked responses. Neither VIP nor dbcAMP were able to inhibit InsP3-evoked repetitive Ca2+ pulses. VIP in a low concentration can generate cytosolic Ca2+ oscillations via cyclic AMP, but high VIP concentrations inhibit both ACh and VIP-evoked Ca2+ signals and this effect is mediated by high intracellular cyclic AMP levels.