Our aim was to determine whether vagal transmission is required for the hormonal response to insulin-induced hypoglycemia in 18-h-fasted conscious dogs. Hollow coils were placed around the vagus nerves, with animals under general anesthesia, 2 wk before an experiment. On the day of the study they were perfused with -15 degrees C ethanol for the purpose of blocking vagal transmission, either coincident with the onset of insulin-induced hypoglycemia or after 2 h of established hypoglycemia. In a separate study the coils were perfused with 37 degrees C ethanol in a sham cooling experiment. The following parameters were measured: heart rate, arterial plasma glucose, insulin, pancreatic polypeptide, glucagon, cortisol, epinephrine, norepinephrine, glycerol, free fatty acids, and endogenous glucose production. In response to insulin-induced hypoglycemia (42 mg/dl), plasma glucagon peaked at a level that was double the basal level, and plasma cortisol levels quadrupled. Plasma epinephrine and norepinephrine levels both rose considerably to 2,135 +/- 314 and 537 +/- 122 pg/ml, respectively, as did plasma glycerol (330 +/- 60%) and endogenous glucose production (150 +/- 20%). Plasma free fatty acids peaked at 150 +/- 20% and then returned to basal levels by the end of the study. The hypoglycemia-induced changes were not different when vagal cooling was initiated after the prior establishment of hypoglycemia. Similarly, when vagal cooling occurred concurrently with the initiation of insulin-induced hypoglycemia (46 mg/dl), there were no significant differences in any of the parameters measured compared with the control. Thus vagal blockade did not prevent the effect on either the hormonal or metabolic responses to low blood sugar. Functioning vagal afferent nerves are not required for a normal response to insulin-induced hypoglycemia.