To explore the relationship between insulin resistance and hypertension, we examined whether acute induction of hypertension can engender insulin resistance. For this purpose we measured rates of insulin-mediated glucose uptake in awake unstressed rats with the euglycemic hyperinsulinemic (12 microns.kg-1.min-1) clamp technique during infusions of saline alone or after induction of hypertension by bolus administration of NG-monomethyl-L-arginine (L-NMMA, 30 and 15 mg/kg), a competitive inhibitor of nitric oxide synthase. Arterial pressure was approximately 20% greater with L-NMMA bolus than with saline alone. Isotopically determined steady-state rates of glucose uptake were 36 +/- 1 mg.kg-1.min-1 during saline alone and 26 +/- 2 and 19 +/- 1 mg.kg-1.min-1 with low- and high-dose L-NMMA (P < 0.001 vs. saline), respectively. To rule out that insulin resistance induced by L-NMMA was adrenergically mediated, clamp studies were repeated with alpha- and beta-blockade. Rates of glucose uptake remained approximately 20% below those observed with saline alone (P < 0.001). A significant inverse correlation was observed between the height of the blood pressure and the rate of glucose uptake (r = 0.32, P = 0.04). In conclusion, acute induction of hypertension with L-NMMA can cause marked insulin resistance. We postulate that reduced skeletal muscle perfusion and/or sympathetic nervous system activation may contribute to insulin resistance induced by L-NMMA.