Insulin-binding sites exist in the lower brain stem of the rat, raising the possibility that the circulating hormone may have cardiovascular and gastric effects at this site. Therefore, we investigated the autonomic effects of applying rat insulin to the surface of the dorsal medulla (0.3 and 3 µU/rat) or microinjecting it into the dorsal vagal complex (DVC) (0.1-10 nU/site) in anesthetized rats. Application of rat insulin to the surface (3 µU/rat) and its microinjection into the DVC (1 and 10 nU/site) both evoked marked, albeit transient, increases in intragastric pressure, pyloric and greater curvature contractile activity, and blood pressure. Much higher doses of human (100 mU) and porcine insulin (3 mU) were needed to evoke modest changes in gastric motor and cardiovascular function when applied to the surface of the dorsal medulla. In addition, a 1,000-fold higher dose of porcine insulin (10 µU) in the DVC was not enough to mimic the autonomic effects of rat insulin microinjected into the same site. The excitatory gastric motor effects of rat insulin in the lower brain stem were abolished by vagotomy, whereas spinal cord transection blocked insulin-evoked increases in blood pressure. To test whether the gastric motor effects of rat insulin in the lower brain stem were caused by potential contamination with pancreatic polypeptide, we microinjected rat pancreatic polypeptide into the DVC at a single dose of 2 pmol. Only a modest increase in intragastric pressure in response to the hormone was observed. Thus it is likely that insulin, through its action in the lower brain stem, may be implicated in the pathogenesis of gastrointestinal and cardiovascular complications in hyperinsulinemia. In addition, species variations in the amino acid sequence of insulin may affect its biological activity in the brain of different species.