Peptide YY (PYY) and neuropeptide Y (NPY) are peptides of 36 amino acids that share structural homologies with pancreatic polypeptide (PP). PP is predominantly found in the endocrine pancreas. PPY is primarily found in mucosal endocrine cells of the distal ileum, colon, and rectum, whereas NPY is found in both the peripheral and central nervous systems. Previous studies indicate that these peptides can interact with the autonomic nervous system. The objective of the present experiments was to study the effect of PYY on neurally stimulated insulin release [i.e., in response to 2-deoxy-D-glucose (2-DG), a nonmetabolizable glucose analogue] in conscious dogs. Intravenous administration of PYY (100, 200, and 400 pmol.kg-1.h-1) reduced 2-DG-stimulated insulin release in a dose-dependent manner (P less than 0.05) without affecting plasma glucose levels. Administration of NPY (800 pmol.kg-1.h-1), but not PP (400 pmol.kg-1.h-1), reduced 2-DG-stimulated release of insulin (P less than 0.05). The inhibitory action of PYY on 2-DG-stimulated insulin release persisted in the presence of atropine or phentolamine treatment; however, hexamethonium alone or phentolamine plus propranolol treatment blocked the inhibitory action of PYY. Release of insulin stimulated by the beta-agonist isoproterenol was also inhibited by PYY (P less than 0.05). These results indicate that PYY can inhibit autonomic neurotransmission by a mechanism that may involve ganglionic or postganglionic inhibition of beta-adrenergic stimulation. Our findings suggest a role for PYY and NPY in the autonomic regulation of insulin release.