hERG activators increase the rapid delayed rectifier K+ current IKr and have been proposed as therapeutic interventions for reducing arrhythmias associated with prolongation of the ventricular action potential, as seen in heart failure (HF) and long QT syndrome 2 (LQT2) for example. However, we have shown that one hERG activator, NS1643, can have pro-arrhythmic side effects as it increases transmural dispersion of repolarisation (TDR) and, therefore, increases vulnerability to re-entrant arrhythmias (Peitersen et al., 2008). Furthermore, NS1643 can block IKr at higher concentrations (Bilet & Bauer, 2012). The novel hERG activator MC-II-157c does not block IKr at higher concentrations, but it can block the Na+ current INa (Guo et al., 2014). We used computational models to simulate MC-II-157c effects on TDR and quantify the interactions of IKr activation and INa block on vulnerability to re-entry. A model of human ventricular cell electrophysiology (O’Hara et al., 2011) was used, with modifications to simulate HF or LQT2. MC-II-157c effects were modelled by modifying the IKr formulation (conductance decreased by 12%, activation shifted by -14 mV and inactivation by 14 mV, and deactivation slowed 3.3-fold) and blocking INa by up to 90%. These cell models were incorporated into a one-dimensional model of the heterogeneous left ventricular wall, which was used to map out the vulnerable window (VW), the spatiotemporal region where an extra stimulus applied during the repolarisation phase results in unidirectional propagation block (Benson et al., 2011). In single HF cells paced to 1 Hz periodic steady-state, TDR was 190 ms. The IKr modification alone decreased TDR to 148 ms, mainly by decreasing midmyocardial action potential duration (APD). 50% INa block alone decreased TDR to 179 ms, due to an increased epicardial APD. MC-II-157c (i.e. the IKr modification with 50% INa block) decreased TDR to 148 ms through a combination of reduced midmyocardial APD and increased epicardial APD. In the HF tissue model (TDR = 85 ms) the same pattern of TDR reduction as in single cells was observed: TDR for IKr modification = 85 ms, for 50% INa block = 79 ms and for MC-II-157c = 60 ms. INa block exerted an additional decrease in TDR through slowed transmural activation: epicardial tissue was excited, and thus repolarised, later. Accordingly, the maximum temporal width of the VW decreased with IKr modification and with 50% INa block (from 35.7 ms to 19.0 and 25.8 ms respectively), and these reductions were enhanced when both effects were combined as in MC-II-157c, when VW = 14.3 ms. Qualitatively similar results were found for the LQT2 model. Thus, we found that the hERG activator MC-II-157c reduces vulnerability to re-entrant arrhythmias due to the cumulative effects of IKr activation and INa block.