1. Calcium/calmodulin-dependent protein kinase II (CaMKII) has an important function in mediating insulin release but its role in the development of diabetes-induced cardiovascular complications is not known. 2. We investigated the ability of a chronic administration of KN-93 (5 mg kg(-1) alt diem for 4 weeks), an inhibitor of CaMKII, to modulate the altered vasoreactivity of the perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes. 3. The vasoconstrictor responses induced by noradrenaline (NE), endothelin-1 (ET-1), and angiotensin II (Ang II), were significantly increased whereas, vasodilator responses to carbachol and histamine were significantly reduced in the perfused mesenteric bed of the STZ-diabetic rats as compared with non-diabetic controls. 4. Inhibition of CaMKII by KN-93 treatment did not affect blood glucose levels but produced a significant normalization of the altered agonist-induced vasoconstrictor and vasodilator responses. KN-93 did not affect agonist-induced responses in control animals. In addition, KN-93 significantly reduced weight loss in diabetic rats. 5. The present data suggest that CaMKII is an essential mediator in the development of diabetic vascular dysfunction and may also play an important role in signalling pathways leading to weight loss during diabetes.