The administration of cyproheptadine (25 mg/kg; i.p.) resulted in an increase of plasma insulin and glucagon (measured using 30 K antibody) 30, 60 and 120 min after injection to fasted rats. This dose of cyproheptadine also induced a hyperglycemia whereas a lower dose (5 mg/kg; i.p.), which did not alter plasma hormone levels, was associated with a hypoglycemia. Fed rats showed a reduction of plasma insulin with a similar elevation of blood glucose after cyproheptadine. Administration of an exogenous load of arginine resulted in increases of plasma insulin and glucagon of a greater magnitude than induced by cyproheptadine, however, cyproheptadine pretreatment (25 mg/kg) completely suppressed the pancreatic response to the amino acid, resulting in blood hormone levels similar to values seen after cyproheptadine administered alone. Cyproheptadine pretreatment also prevented the hyperinsulinemia and hypoglucagonemia resulting from glucose loading. alpha-Adrenergic receptor blockade (with phentolamine), beta adrenergic receptor blockade (with propranolol) and adrenodemedullation did not alter pancreatic responsiveness to the drug.