Besides vagal cholinergic mechanisms, pancreatic polypeptide (PP) secretion is thought to be mediated by hormones. This study was performed to delineate the role of extrinsic pancreatic innervation and cholecystokinin (CCK) in amino acid- and fat-stimulated PP secretion. In ten mongrel dogs, pancreatic denervation was performed by the method of Debas et al. [3]. Total denervation of the pancreas did not alter PP response to intraduodenal application of amino acids (integrated output 24,434 +/- 3260 pmol/1 x 120 min before vs 22,797 +/- 2470 pmol/1 x 120 min after operation) and to intraduodenal fat solution (19,595 +/- 2121 pmol/1 x 120 min vs 19,983 +/- 2031 pmol/1 x 120 min). Also, no significant differences were measured in CCK release (491 +/- 71 pmol/1 x 120 min vs 430 +/- 57 pmol/1 x 120 min for amino acids, 571 = 63 pmol/1 x 120 min vs 563 +/- 89 pmol/1 x 120 min for fat solution). Plasma PP and CCK levels were compared by linear regression analysis. Correlations between PP and CCK were high in the intact pancreas (amino acids, r = 0.92; fat, r = 0.99) as well as in the denervated pancreas (r = 0.93 amino acids and r = 0.98 fat). These results show that extrinsic pancreatic innervation does not influence PP and CCK release after intraduodenal amino acids or fat solution and that PP secretion seems to be mediated to some extent through the release of CCK.