We examined the influence of chronic treatment with KN-93 (an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), 5 mg/kg given every other day for 4 weeks) on mean arterial pressure (MAP), urine protein and vascular reactivity in streptozotocin (STZ)-induced diabetes in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Treatment with KN-93 did not cause any significant changes in body weight, blood glucose or MAP in any of the groups studied. However, diabetes-induced elevations in urine volume and protein were significantly attenuated in KN-93-treated animals. KN-93-mediated decrease in urine volume and protein was more pronounced in SHR compared to WKY rats. The increased vascular responsiveness to endothelin-1 and angiotensin II in isolated carotid arteries from STZ-treated WKY (D-WKY) and SHR (D-SHR) was normalized by chronic treatment with KN-93. Furthermore, chronic treatment with KN-93 significantly prevented the development of diabetes-induced endothelial dysfunction as impaired endothelium-mediated vascular relaxation to carbachol and histamine under diabetic conditions was reversed by parallel treatment with the inhibitor. These results suggest that signal transduction involving CaMKII contributes to the development of abnormal vascular reactivity and renal dysfunction during simultaneous occurrence of hypertension and diabetes. We conclude that inhibition of CaMKII-mediated signalling could be an effective way to antagonize the elevated activities of injury-promoting factors in diabetic patients with hypertension.