This study was performed to examine the role of nitric oxide in the effects of hypoglycemia on the cerebral circulation. Hypoglycemia was induced with insulin and its effects on cerebral blood flow (measured with an electromagnetic flow transducer placed on the internal maxillary artery) were studied in awake goats under control conditions and after administration of the nitric oxide synthesis inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 47 mg/kg). Also, cerebrovascular reactivity to vasodilator stimuli was examined during insulin-induced severe hypoglycemia, before and after L-NAME treatment. In five animals under control conditions (glycemia = 90 +/- 7 mg/dl, cerebral blood flow = 64 +/- 4 ml/min, mean systemic arterial pressure = 102 +/- 4 mmHg, cerebrovascular resistance = 1.62 +/- 0.11 mmHg/ml per min and heart rate = 73 +/- 6 beats/min), insulin decreased glycemia: when hypoglycemia was moderate (glycemia = 46 +/- 2 mg/dl) or severe (glycemia = 26 +/- 1 mg/dl) cerebral blood flow increased by 25 +/- 4% and 47 +/- 6%, and cerebrovascular resistance decreased by 18 +/- 3% and 34 +/- 4%, respectively. Under basal conditions, L-NAME did not affect glycemia but reduced resting cerebral blood flow by 37 +/- 2%, increased mean arterial pressure by 33 +/- 2% and decreased heart rate by 28 +/- 3%; after L-NAME, both moderate and severe hypoglycemia did not alter significantly resting cerebral blood flow and cerebrovascular resistance. In five other goats, L-NAME, administered during severe hypoglycemia, abolished the increase in cerebral blood flow, and increased cerebrovascular resistance and mean arterial pressure over the control (normoglycemic) values. In these animals with severe hypoglycemia, acetylcholine (0.01-1 microg), isoproterenol (0.03-3 microg) and diazoxide (0.3-9 mg), injected into the internal maxillary artery, decreased cerebrovascular resistance in a dose-dependent manner, and this decrease was similar before and after L-NAME. Therefore, insulin-induced hypoglycemia may produce cerebral vasodilatation by releasing nitric oxide and may diminish the capacity of the cerebral vasculature to release nitric oxide in response to acetylcholine.