The purpose of this study was to evaluate the roles of vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), and glucagon in the local regulation of the lipid-induced intestinal hyperemia. Total blood flow and the arteriovenous hormone concentration gradient were measured in isolated jejunal loops of anesthetized dogs with either saline, bile (10% in normal saline), oleic acid (40 mM in normal saline), or oleic acid and bile in the lumen. The bile-oleic acid mixture increased both blood flow (+21 +/- 7%) and VIP release (+118 +/- 7%), while CCK release was considerably less. There was a transient rise in glucagonlike immunoreactivity but no change in pancreatic glucagon release. Neither bile nor oleic acid alone altered either local blood flow or hormone release. Infusion of VIP into the arterial circulation of the jejunum significantly reduced vascular resistance (-11 +/- 4%) but at a dose (150 ng . min-1 X 100 g-1) 10 times that released in response to the bile-oleic acid mixture. This study indicates that oleic acid increases both blood flow and intestinal hormone production only when present in the lumen in micellar form and suggests that VIP could play a role in the jejunal vascular response to fat.