The effect of pancreastatin on the release of insulin, glucagon, and somatostatin was studied in the isolated perfused rat pancreas. After an initial equilibration period (-20 to 0 min) with a basal glucose concentration (3.3 mM), the pancreata were perfused with either 16.7 mM glucose (0-40 min) or with 20 mM arginine (0-20 min). Pancreastatin was introduced 10 min prior to and throughout the administration of the high glucose and arginine and continued during their perfusion. As expected, the glucose and the arginine augmented insulin and somatostatin release. Pancreastatin (1 and 10 nM) markedly suppressed the first phase of insulin release with both insulinogogues used, while the early somatostatin secretion was not significantly decreased. However, the peak incremental somatostatin response to arginine was reduced by 50% (P less than 0.05). Conversely, the peptide (10 nM) tended to augment arginine-induced glucagon release. Pancreastatin (100 nM) also suppressed glucose-stimulated insulin release from isolated rat islets. These pancreastatin-mediated alterations in islet hormone release are reminiscent of those known to characterize non-insulin-dependent diabetes. Therefore, the significance of pancreastatin in islet physiology and pathophysiology deserves special consideration.