The effects of local and peripheral administration of cholecystokinin-8 (CCK-8) and secretin on the interdigestive pancreatic secretion were examined in conscious preruminating calves. Six calves were surgically fitted with a pancreatic catheter and duodenal cannula, duodenal electrodes and strain gauges, and cooling devices on the cervical vagi. Local intra-arterial (I.A.) infusions were made into the duodenal branch of the right gastroepiploic artery, and peripheral infusions (I.V.) into the external jugular vein. CCK-8 and secretin were infused I.A. and I.V. for 5 min (0, 10, 30 and 100 pmol (kg body weight)-1) during the asecretory phase of the pancreatic interdigestive cycle. CCK-8 and secretin at 100 pmol kg-1 were administered concomitant with reversible cold vagal blockade. Local infusion of CCK-8 without vagal blockade resulted in a significantly faster and stronger pancreatic response than the respective peripheral infusion, although CCK in peripheral blood plasma was paradoxically only minimally increased after I.A. CCK-8 in comparison with a marked increase after I.V. CCK-8. Vagal blockade noticeably decreased the pancreatic response for I.A. CCK-8, but not for I.V. CCK-8. Secretin produced similar pancreatic responses after I.V. and I.A. administration, but the plasma secretin concentration in peripheral blood was markedly lower after I.A. than after I.V. infusions. Cold vagal blockade uniformly reduced the stimulatory effect of I.A. and I.V. secretin infusion on the exocrine pancreas. In calves, CCK-8 apparently stimulates the exocrine pancreas by two different mechanisms: by a direct effect that is vagally independent as well as by an indirect effect in the duodenum that is vagally dependent. The indirect effect of secretin in the duodenum is less clear, but both direct and indirect effects of secretin depend on vagal integrity.