The human vasoactive intestinal polypeptide (VIP) precursor contains a sequence, a peptide with an N-terminal histidine and C-terminal methionine (PHM), which is 93% homologous to the porcine intestinal peptide, (PHI) a peptide having N-terminal histidine and C-terminal isoleucine amide, suggesting that PHI could be a product of the porcine VIP precursor. If so, VIP-producing nerves would be expected to produce and release PHI in addition to VIP. We studied this in the pig pancreas. By immunohistochemistry, we identified nerve cell bodies in local ganglia and nerve fibers that were both PHI and VIP immunoreactive, innervating exocrine as well as endocrine structures. During electrical stimulation of the vagus nerve supply to the isolated perfused pig pancreas, a synchronous and approximately equimolar release of immunoreactive PHI and VIP was observed. Both responses were abolished by hexamethonium and could be copied by cholinergic agonists. Infusions of PHI and VIP at 10(-9) M stimulated the exocrine secretion of fluid and bicarbonate, and the effect of a combination of the two peptides was additive. In addition, both peptides stimulated insulin as well as glucagon secretion. By gel chromatography the VIP immunoreactivity in the venous effluent corresponded precisely to synthetic VIP, but only 24% of the PHI immunoreactivity corresponded to synthetic PHI; a larger peptide (mol wt 5,000-7,000) was responsible for the majority. The biological activity of this component is unknown. The results suggest that both VIP and PHI, released from intrapancreatic nerve fibers, participate in the parasympathetic control of pancreatic secretion.