The aims of this study were to study the influence of the duration of diabetes, the role of endothelial derived vasodilators and the role of phosphodiesterase (PDE) isoform activity, in the early changes in vascular reactivity of aortic rings from diabetic rats. Diabetes mellitus was induced in female rats by i.v. streptozotocin (85 mg/kg). Two or 4 weeks later, thoracic aortic rings from control and diabetic rats were isolated and vascular responses to acetylecholine (Ach), SNAP (NO donor), DMPPO (PDE5 inhibitor), and phenylephrine (PE), were obtained in the presence and absence of endothelium or other drugs. PDE isoform activity was also measured. At 2 weeks, responses to Ach and DMPPO were enhanced while those to PE were attenuated in diabetic rats relative to controls. Indomethacin and SQ29548 (a TXA₂ receptor antagonist), but not L-NAME, corrected these differences. The responses to SNAP, and cAMP and cGMP hydrolytic activities, were similar in the two groups. In contrast, at 4 weeks, Ach, DMPPO, and PE produced similar responses in the two groups; L-NAME rendered the response to PE lower in the diabetic group, and this was corrected by indomethacin, but not SQ 29548, treatment. The response to SNAP was greater in the diabetic group, and this was corrected by DMPPO. Activity of all PDE's was decreased at 4 weeks. We conclude that at 2 weeks, there is modulation of TXA₂ production but no change in the NO system or PDE isoform activities. At 4 weeks, a reduction in NO activity is superimposed; at this stage, PDE activity is reduced together with increased production of vasodilating prostaglandins, possibly as a compensatory mechanism to maintain normal vascular reactivity.