We investigated the responsiveness of isolated diabetic and normal rabbit aortic strips to norepinephrine. Alloxan, 160 mg/kg, was administered intravenously 1 mo before experiments were performed. Helically cut thoracic aortic strips from diabetic and control animals were suspended side by side in the same muscle bath. The maximum contractile response to norepinephrine of diabetic strips was 68 +/- 5% of control in eight pairs of animals (P less than 0.001). This differential response was not changed by propranolol or cocaine, indicating that it is not explained by either enhanced beta receptor activity or more avid uptake of norepinephrine by nerve endings. Tyramine responses displayed the same differential, suggesting that endogenous release of norepinephrine also results in a lower response of diabetic aortic strips. Maximum responses to KCl were also markedly depressed in strips from nine diabetic rabbits (P less than 0.005). This indicates that the diabetes-induced changes occur at a stage in contraction beyond alpha-receptor activation.