The effects of pancreatic polypeptide, thyrotropin-releasing hormone, and glucagon on plasma amino acid uptake by the exocrine pancreas were studied in 12 healthy volunteers aged 22-31 years. Pancreatic amino acid uptake was determined by measuring free plasma amino acid concentration before and during pancreatic stimulation with cerulein (50 ng/kg.h). The administration of this peptide caused a significant decrease (by 14%-20%) in plasma amino acid concentration. Pancreatic polypeptide and thyrotropin-releasing hormone, given at respective doses of 195 pmol/kg.h and 2 micrograms/kg.h, significantly prevented this decrease by 79.3% and 55.8%, respectively. Glucagon, administered at a dose of 7.5 micrograms/kg.h, significantly augmented (by 68.8%) the decreasing effect of cerulein on plasma amino acid concentration. In 2 patients with severe exocrine pancreatic insufficiency, cerulein had no effect on the concentration of plasma amino acids, whereas the addition of glucagon caused a marked decrease. The results indicate that pancreatic polypeptide and thyrotropin-releasing hormone are able to inhibit plasma amino acid uptake by pancreatic acinar cells; this inhibitory effect could be a mechanism by which these peptides decrease pancreatic enzyme secretion. Glucagon does not seem to affect pancreatic amino acid uptake, at least not under the experimental conditions of this study. The decrease in plasma amino acid concentration following glucagon administration was likely the result of the stimulation of amino acid uptake by extrapancreatic tissues by this peptide.