The autocrine modulation of cardiac K⁺ currents was compared in ventricular (V) and atrial (A) cells from type1 diabetic rats. K⁺ currents were measured using whole cell voltage clamp. Angiotensin II (ANG II) was measured by ELISA and immunofluorescent labeling. Oxidative stress was assessed by immunofluorescent labeling with dihydroethidium (DHE), a measure of superoxide ions. In V cells, K⁺ currents are attenuated following activation of the renin-angiotensin system (RAS) and the resulting ANG II-mediated oxidative stress. In striking contrast, these currents are not attenuated in A cells. Inhibition of the angiotensin-converting enzyme (ACE) also has no effect, in contrast to current augmentation in V cells. ANG II levels are enhanced in V, but not in A cells. However, the high basal ANG II levels in A cells suggest that ANG II-mediated pathways are suppressed, rather than ANG II formation. Concordantly, superoxide ion levels are lower in diabetic A than V cells. Several findings indicate that high atrial natriuretic peptide (ANP) levels in A cells inhibit RAS activation: In male diabetic V cells, in vitro ANP (300 nM - 1 µM, >5h) decreases oxidative stress and augments K⁺ currents, but not when excess ANG II is present. ANP has no effect on ventricular K+ currents when the RAS is not activated, as in control males, in diabetic males treated with ACE inhibitor, and in diabetic females. In conclusion, the modulation of K⁺ currents and oxidative stress is significantly different in A and V cells in diabetic rat hearts. The evidence suggests that this is largely due to inhibition of RAS activation and/or action by ANP in atrial cells. These results may underlie chamber-specific arrhythmogenic mechanisms.