To determine if galanin is released during pancreatic neural activation, we measured galanin-like immunoreactivity (GLIR) in pancreatic venous and peripheral arterial plasma during 10 min of electrical stimulation of the mixed autonomic pancreatic nerves in halothane-anesthetized dogs, using a sensitive and specific radioimmunoassay. During mixed pancreatic nerve stimulation (MPNS), pancreatic venous GLIR increased by 174 +/- 20 fmol/ml, whereas arterial GLIR did not change. By use of the arteriovenous concentration difference and measurements of pancreatic venous blood flow, pancreatic spillover of GLIR was calculated and found to increase by 640 +/- 90 fmol/min during MPNS. This MPNS inhibited the output of immunoreactive insulin (IRI; delta = -53 +/- 9%) and somatostatin-like immunoreactivity (SLI, delta = -49 +/- 13%) and stimulated that of immunoreactive glucagon (IRG, delta = +600 +/- 200%). To determine if the amount of GLIR released during MPNS was sufficient to elicit these changes of pancreatic hormone secretion, we compared the effect of MPNS on IRI, SLI, and IRG output with the effect of synthetic galanin infused directly into the pancreatic artery at a rate that reproduced the MPNS-induced spillover of GLIR. Exogenous infusion of synthetic galanin (2.7 pmol/min) increased pancreatic venous levels of GLIR by 169 +/- 38 fmol/ml, did not change arterial GLIR levels, and thus increased calculated spillover (appearance) by 550 +/- 160 fmol/min, which was nearly identical to the increment produced by MPNS. This matched infusion of galanin inhibited IRI (delta = -58 +/- 3%) and SLI output (delta = -35 +/- 3%) and modestly stimulated IRG output (delta = +62 +/- 10%).(ABSTRACT TRUNCATED AT 250 WORDS)