OBJECTIVES: The current study aims to investigate the possible role of NO distillate either for therapeutic or for protective potential in diabetic cardiomyopathy. BACKGROUND: Protective and restorative effects of distillated Nerium oleander (NO) on the diabetes-induced electrophysiological and structural alterations were investigated. METHODS: Type 2 diabetes was induced by combination of single dose streptozotocin injection and high fat diet for four weeks. Experimental groups were designed as follows: control, diabetic, restorative-NO treated diabetic and protective-NO treated diabetic. Intracellular action potentials (AP) and contractile activities were measured form left ventricular papillary muscle strips as well as histopathological examination of heart tissue and biochemical examinations of serum were performed. RESULTS: Type 2 diabetes induced AP prolongation was prevented with both ways of NO treatments. Moreover, treatments produced nearly complete restorations of diabetes-induced depressed amplitude and altered kinetics of contractile activities. In parallel to electrophysiological parameters, both histopathological and biochemical results indicates the NO induced benefi cial effects on the diabetes related alterations. CONCLUSION: Distillated Nerium oleander (NO) can be a highly potential therapeutic or preventive agent on the diabetes induced excitation-contraction coupling alterations (Tab. 3, Fig. 3, Ref. 23).