It has been reported that substance P influences plasma glucagon concentrations; some investigators reported elevation of glucagon but the results are conflicting. This might be due to the differences in the species of experimental animal, dose of administered substance P, study system (in vivo or in vitro), and other experimental conditions. In this study, various doses of substance P were infused into the superior pancreaticoduodenal artery of anesthetized mongrel dogs for 30 min. Plasma glucagon and insulin concentrations in the superior pancreaticoduodenal (pancreatic) vein were measured by radioimmunoassay. For measuring plasma glucagon, 30K antibodies were used. Substance P (100 ng/kg body weight/min) infusion brought about mild hypoglycemia. A rapid and significant increase of plasma glucagon level was observed shortly after sub-stance P administration, then plasma glucagon concentrations decreased transiently during the next 10 to 20 min. Gradual increase to a high plateau level followed after discontinuation of the drug. A small transient decrease of plasma insulin level was seen at the beginning of the experiment. Blood pressure decreased during substance P infusion. Impedance in pancreatic tissue was markedly lowered. The lowered impedance reflects increased blood flow in the tissue. Administration of 25 or 50 ng/kg/min of substance P induced mild lowering of blood glucose and plasma insulin, but increase of plasma glucagon. The infusion of substance P at a dose of 5 ng/kg/min for 30 min did not cause any changes in blood glucose, plasma glucagon or insulin levels. But, after discontinuation of the drug, the plasma glucagon level gradually rose to a significantly high level. Blood pressure was not affected, but impedance in pancreatic tissue showed a gradual, marked decrease. During substance P infusion at a dose of 0.5ng/kg/min, blood-parameters did not vary. After ceasing the infusion, the plasma glucagon level gradually increased. In conclusion, substance P was thought to stimulate dose-related glucagon secretion not only by a neurogenic circulatory action, but also by a direct action on pancreatic alpha cells. The increase in glucagon concentration in the later part of the experiments might be caused by vaso-circulatory changes and other hormonal pharmacological actions of substance P.