The secretion of pancreatic polypeptide (PP) by neuropeptides [vasoactive intestinal polypeptide, gastrin-releasing peptide (GRP), neuromedin B, and neuromedin C] and carbachol was investigated using the isolated perfused ventral part of the rat pancreas, with or without atropine, and a specific radioimmunoassay for rat PP. The release of PP from the dorsal part of the rat pancreas by GRP and carbachol was also studied. Carbachol and GRP stimulated, in a dose-dependent manner ranging from 10(-6) to 10(-9) M, PP secretion from the ventral part of the pancreas. Maximum responses were observed with 10(-7) to 10(-8) M carbachol and 10(-7) M GRP. The response with 10(-7) M carbachol was biphasic and was abolished by 10(-5) M atropine. The response with 10(-7) M GRP, however, was transient, monophasic, and not inhibited by atropine. Vasoactive intestinal polypeptide (10(-7) M) stimulated a weak PP secretion that was not inhibited by atropine. The potency of GRP and vasoactive intestinal polypeptide relative to carbachol at 10(-7) M was 24% and 7%, respectively. Neuromedin C had almost the same bioactivity as GRP with respect to the release of PP, whereas neuromedin B was one-third less potent than GRP and neuromedin C. The relative secretion of PP from the dorsal compared with the ventral part of the pancreas after stimulation by 10(-7) M carbachol and GRP was 19% and 22%, respectively. These data show that peptidergic nerves may play some role in PP secretion. In addition, the main source of PP to the systemic circulation may be the ventral part of the pancreas.