The pituitary adenylyl cyclase-activating polypeptide PACAP-(1-38) has potent pancreatic secretory effects. We studied its immunohistochemical localization, release, and contribution to secretion induced by electrical vagus stimulation using isolated perfused porcine pancreas and the PACAP receptor antagonist PACAP-(6-38) (10(-7) M). PACAP was found in nerve fibers throughout the pancreas but, in particular, encircling ganglionic vasoactive intestinal polypeptide (VIP)-positive nerve cell bodies and, mostly, colocalized with VIP. Vagus stimulation caused its release. PACAP-(1-38)(4 x 10(-9) M) stimulated exocrine and endocrine secretion and released VIP. PACAP-(6-38) decreased PACAP-induced flow of juice to 59 +/- 7.8% and insulin secretion and VIP release to 12 +/- 6.8 and 57 +/- 13%, respectively. Glucagon secretion was unaffected. PACAP-(6-38) reduced vagus-stimulated flow rate to 63 +/- 7.6%, insulin and glucagon responses to 31.8 +/- 13 and 6 +/- 4%, respectively, and VIP release to 23 +/- 8.4% and reduced VIP-induced (2 x 10(-9) M) juice and insulin (but not glucagon) outputs to 8.3 +/- 4.2 and 67 +/- 14%, respectively. In conclusion, 1) pancreatic PACAP fibers seem to activate intrapancreatic VIPergic neurons, 2) PACAP-(6-38) antagonism documents the role of VIP/PACAP for neural regulation but cannot distinguish their relative importance, and 3) a PACAP receptor with low affinity for PACAP-(6-38), associated with glucagon cells, may exist.