Contractile responses of aortas and mesenteric arteries from control and 3 month streptozotocin-diabetic rats to alpha-adrenoceptor agonists were compared in the presence and absence of endothelium. In the presence of endothelium, responses of both arteries from diabetic animals to norepinephrine and methoxamine were enhanced compared to control, although no response to clonidine could be detected in arteries from either control or diabetic animals. Following endothelium removal, no significant differences were found between control and diabetic arteries in maximum contractile responses to noradrenaline or methoxamine. However, the sensitivity (pD2) of diabetic aortas to these two agonists was significantly increased, while maximum responses of diabetic aortas and mesenteric arteries to clonidine were much greater than control. In addition, no differences between control and diabetic aortas were detected when cGMP levels were measured in the absence and presence of acetylcholine. These results suggest that enhanced responsiveness of arteries from diabetic animals to alpha-adrenoceptor stimulation is not the result of a decrease in endothelium-derived relaxing factor (EDRF) release in diabetic blood vessels.