Synthetic cyclic somatostatin was infused into either the cranial pancreaticoduodenal artery or the femoral vein of anesthetized dogs with or without previous administration of phentolamine. Somatostatin infused into the pancreatic artery at a dose of 50 ng/kg/min for 10 min caused significant decreases in blood flow and plasma basal concentrations of both glucagon and insulin in the cranial pancreaticoduodenal vein, resulting in a profound decline of bihormonal output during the infusion. Arterial plasma glucose was not reduced during the administration of somatostatin in the pancreatic artery. These somatostatin-induced decreases failed to be eliminated by a 0.2 mg/kg injection of phentolamine into the femoral vein followed by a 9-min infusion of this alpha-adrenergic blocker (0.02 mg/kg/min) into the pancreatic artery immediately prior to the somatostatin administration. An inhibition of glucagon and insulin output and a fall of plasma glucose caused by somatostatin (1.7 microgram/min) infused into the femoral vein for 30 min also were not abolished by a prolonged and simultaneous infusion of phentolamine (0.2 mg/min) into the femoral vein over a period of 2 hr. These results indicate that alpha-adrenergic receptor mechanisms do not play a major role in the inhibition of islet glucagon and insulin secretion by somatostatin.