The purpose of this study was to investigate the glucose dependency of arginine vasopressin (AVP)-induced insulin, glucagon, and somatostatin release from the perfused rat pancreas. AVP (30 or 300 pmol/L) was tested in the presence of a glucose concentration of 0, 1.4, 5.5 (basal level), or 20 mmol/L. The rates of insulin release at 0 and 1.4 mmol/L glucose were approximately 70% to 80% and 60% to 70% less, respectively, than that at the baseline level. AVP (30 or 300 pmol/L) failed to change insulin release at 0 and 1.4 mmol/L glucose. At the basal glucose level, AVP (300 pmol/L) induced a biphasic insulin release, a peak followed by a sustained phase. In addition, the combination of glucose (20 mmol/L) and AVP (300 pmol/L) induced a higher insulin peak and sustained phase than 20 mmol/L glucose alone. The rates of glucagon release at 0 and 1.4 mmol/L glucose were about 3- and 2-fold more, respectively, than that at the baseline level. At 0 and 1.4 mmol/L glucose, both 30 and 300 pmol/L AVP caused a higher glucagon peak and sustained phase than 0 and 1.4 mmol/L glucose alone. At the basal glucose level, AVP (30 or 300 pmol/L) induced a biphasic glucagon release, a peak followed by a sustained phase. The rate of glucagon release at 20 mmol/L glucose was approximately 60% to 70% less than that at the baseline level. When AVP (300 pmol/L) was administered in 20 mmol/L glucose, it induced a transient glucagon peak, which was 2.4-fold of the baseline level. At all glucose concentrations tested, AVP (30 or 300 pmol/L) failed to change somatostatin release. These results suggested that (1) hypoglycemia directly increases glucagon and decreases insulin release; (2) AVP induces insulin and glucagon release by a direct action on beta and alpha cells, respectively; (3) AVP induces insulin and glucagon release in a glucose-dependent manner-the higher the glucose concentration, the greater the enhancement of AVP-induced insulin release, whereas the lower the glucose concentration, the higher the enhancement of AVP-induced glucagon release; and (4) alpha cells are more sensitive to AVP than beta cells in hormone release.