The ionic current responsible for terminating the action potential (AP), and thereby in part determining the AP duration (APD), is the potassium current (IK), consisting of primarily two components: a rapidly (IKr) and a slowly (IKs) activating delayed rectifier potassium current. The aim of this study was to evaluate potential antiarrhythmic effects of compound induced IKs activation using the benzodiazepine L-364,373 (R-L3). Ventricular myocytes from guinea pigs were isolated and whole-cell current clamping was performed at 35°C. It was found that 1 μM R-L3 significantly reduced the APD90 at pacing frequencies of 1, 2, and 4 Hz when compared to control (40 ± 6%, 22 ± 2%, and 32 ± 2%, respectively). The reduction of APD90 was accompanied by a reduced triangulation (given as APD30-90) when compared to control at all pacing frequencies (62 ± 7 ms vs. 41 ± 3 ms, 55 ± 5 ms vs. 35 ± 6 ms, and 45 ± 4 ms vs. 32 ± 2 ms, at 1 Hz, 2 Hz, and 4 Hz, respectively). The abbreviated APDs also resulted in a reduction in the relative refractory period, and no direct protection against pacing induced early after-depolarizations (EAD) could be observed. However, an increase in repolarizing capacity was seen with 1 μM R-L3, as more complete repolarization of the AP was achieved before EADs could be elicited. Finally, a functional demonstration of the repolarization reserve revealed that increased IKs can counteract a pharmacologically reduced IKr. In conclusion, pharmacological activation of IKs possesses both pro- and antiarrhythmic characters. The most prominent antiarrhythmic propensity is the ability for IKs activation to rescue a cellular model of long QT type 2.