Oxidative stress is an underlying cause of cardiovascular complications including heart failure in individuals with diabetes mellitus. Two classes of oxidants are upregulated during diabetes, reactive oxygen species (ROS) and reactive carbonyl species (RCS). ROS-scavenging based therapies only minimally improved cardiovascular outcomes in clinical studies. This study uses a rat model of type 1 diabetes (streptozotocin 45 mg/kg i.p. in citrate buffer pH 4.5) in conjunction with echocardiography, high speed video edge detection, confocal microscopy, Western blot, [3H]ryanodine binding, Ca2+ uptake assays and treatments with Tempol (TP, a superoxide dismutase mimetic), pyridoxamine (Py, a scavenger of RCS) and aminoguanidine (Ag, a mixed ROS/RCS scavenger) to test the hypothesis that RCS is the primary cause for heart failure development during diabetes. All data are given at mean ± S.E.M. Eight weeks of diabetes reduced cardiac and myocyte fractional shortening by 16.1 ± 1.2% and 19.3 ± 1.1%. Rates of evoked Ca2+ release and reuptake from myocyte sarcoplasmic reticulum (SR) were also slowed by 36.3 ± 6.4% and 176.1 ± 8.2%. Expression of ryanodine receptors (RyR2) and saco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) did not change, but their activities were 40.3 ± 6.1% and 38.8 ± 5.4%, respectively. Six weeks of treatment with TP starting two weeks after the onset of diabetes, did not blunt cardiac and myocyte fractional shortening (18.1 ± 2.0% and 16.5 ± 2.2%), slowing in SR Ca2+ release (27.8 ± 5.1% ), RyR2 activity loss (30.2 ± 4.4%) and SERCA2 activity loss (34.5 ± 2.4%). However, it blunted the slowing SR Ca2+ reuptake rate (75.6 ± 7.2%, P<0.05). Interestingly, Py and Ag treatments blunted reductions in cardiac and myocyte fractional shortening (3.6 ± 1.1% and 9.7 ± 0.6%, and 4.2 ± 0.8%, 8.9 ± 1.2%, P<0.05), the slowing in rate of Ca2+ release from the SR (13.2 ± 2.3% ± 15.1 ± 1.8%, P<0.05), and SR Ca2+ uptake rate (100.5 ± 7.2% and 90.2 ± 9.1%, P<0.05). Tp, Py and Ag treatments did not lower blood glucose and steady state levels of RyR2 and SERCA2 proteins. TP was more efficacious than Py and Ag in reducing serum MDA levels (an index of ROS), but Py and Ag were more efficacious in reducing activity of serum semicarbazide amine oxidase (an index of RCS). Using membrane vesicle preparations, Py, Ag, and Tp were also able to reduce carbonyl adducts on select proteins. From these data we conclude elevation in RCS rather than ROS is the leading cause for heart failure development during diabetes.