We tested the hypothesis that sildenafil, singly or in combination with a nitric oxide donor (NOD) promotes VT and ventricular fibrillation (VF). Vulnerability to VT/VF was tested by rapid pacing in eight isolated normal swine right ventricles (RV). The endocardial activation was optically mapped and the dynamic action potential duration restitution (APD-R) curves constructed with metal microelectrode. At baseline, no VT/VF could be induced. Sildenafil (0.2 µg/ml) or NOD singly or in combination did not alter VT/VF vulnerability. However, when 2 µg/ml sildenafil was combined with a NOD the incidence of VT and VF rose significantly (P<0.01). VT with a single periodic wavefront was induced in 5 out 8 RVs and VF with multiple wavefronts, in all 8 RVs. Sildenafil-NOD pro-VT/VF combination significantly increased the maximum slope of the APD-R curve and the amplitude of the APD alternans. Sildenafil's pro/VT/VF effects were reversible after drug-free Tyrode's perfusion. We conclude that sildenafil (2 µg/ml) and NOD combination increases VT/VF vulnerability in normal RV by a mechanism compatible with the restitution hypothesis.