Introduction: Heart failure and Andersen-Tawil syndrome Type 1 (ATS1), linked to abnormalities of the inward-rectifier potassium current (IK1), are associated with ventricular arrhythmias. It was previously demonstrated that interventricular IK1 heterogeneities underlie QT prolongation and increased arrhythmia induction rates secondary to increased right ventricular (RV) action potential duration (APD) sensitivity to partial IK1 blockade and hypokalemia. We hypothesized that increasing outward potassium current with pinacidil, an ATP-sensitive potassium channel opener, will globally decrease APD, mitigate QT prolongation and attenuate the incidence of arrhythmias. Methods: BaCl2 (10μM) was perfused to reduce IK1 in Langendorff perfused isolated guinea pig whole-heart preparations and extracellular potassium concentration was maintained at 2mM [K+]o (baseline). APD from RV and left ventricle (LV) were quantified by ratiometric-optical voltage (di-4-ANEPPS, n=6) mapping during RV pacing (S1) without or with pinacidil (5, 15 and 30μM). Results: At 400ms basic cycle length (BCL), pinacidil (15μM) significantly decreased RV base (RVB), RV apex (RVA), LV apex (LVA), and LV base (LVB) APD from baseline by 15.7±3.5%, 20.5±6.1%, 11.6±3.6%, and 18.1±6.4% respectively (p<0.05). Importantly, APD dispersion between RVB and LVA (regions demonstrating greatest dispersion at baseline) decreased from 8.0±0.5% to 2.6±0.1% (p<0.001). Moreover, 15μM pinacidil significantly shortened QT interval by 45.8±16.9ms (p<0.05) compared to baseline. At baseline, interventricular repolarization heterogeneities were insufficient to precipitate arrhythmias during premature stimulation (S1-S2); however, 50% (n=8) of animals exhibited spontaneous and/or rapid pacing induced arrhythmias. Notably, pinacidil abolished all spontaneous arrhythmias and decreased the incidence of rapid pacing induced arrhythmias to 6.3% (n=1). Conclusion: These data suggest that increased dispersion of APD secondary to reduced IK1 function serves as a substrate for arrhythmogenesis. Therefore, amelioration of potassium handling deficit in diseases resulting in loss of IK1 function such as heart failure and ATS1 results in mitigation of pro-arrhythmic APD dispersion.