Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba 2+

Sildenafil (Viagra), the first approved and widely used oral drug for the treatment of erectile dysfunction, was occasionally associated with life-threatening ventricular arrhythmias in patients. Since inward rectifier potassium current ( I K1 ) may considerably contribute to this arrhythmogenesis, we investigated the effect of sildenafil on the human Kir2.1 and Kir2.2, the prevailing subunits forming the ventricular I K1 channels. Experiments were performed by the whole-cell patch clamp technique at 37°C using Chinese hamster ovary cells transiently expressing the human Kir2.1 and Kir2.2 channels. Changes of both the inward and outward current components (at −110 and −50 mV, respectively) were tested to be able to consider the physiological relevance of the sildenafil effect (changes at −110 and −50 mV did not significantly differ, results at −50 mV are listed below). A significant Kir2.1 inhibition was observed at all applied sildenafil concentrations (16.1% ± 3.7%, 20.0% ± 2.6%, and 15.0% ± 3.0% at 0.1, 1, and 10 μM, respectively). The inhibitory effect of 0.1 μM sildenafil was potentiated by the presence of a low concentration of Ba 2+ (0.1 μM) which induced only a slight Kir2.1 inhibition by 5.95% ± 0.75% alone (the combined effect was 35.5% ± 3.4%). The subtherapeutic and therapeutic sildenafil concentrations (0.1 and 1 μM) caused a dual effect on Kir2.2 channels whereas a significant Kir2.2 activation was observed at the supratherapeutic sildenafil concentration (10 μM: 34.1% ± 5.6%). All effects were fully reversible. This is the first study demonstrating that sildenafil at clinically relevant concentrations inhibits both the inward and outward current components of the main human ventricular I K1 subunit Kir2.1. This inhibitory effect was significantly potentiated by a low concentration of environmental contaminant Ba 2+ in agreement with recently reported data on rat ventricular I K1 which additionally showed a significant repolarization delay. Considering the similar subunit composition of the human and rat ventricular I K1 channels, the observed effects might contribute to sildenafil-associated arrhythmogenesis in clinical practice.