Combination of Sildenafil and Ba at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation.

Sildenafil (Viagra) is a vasodilator mainly used in the treatment of erectile dysfunction. Atrial or ventricular fibrillation may rarely occur as a side effect during sildenafil therapy. Although changes in inward rectifier potassium currents including are known to contribute to the pathogenesis of fibrillation, the effect of sildenafil on has not been studied. In experiments, Ba is used as a specific inhibitor of at high concentrations (usually 100 µM). Being an environmental contaminant, it is also present in the human body; Ba plasmatic concentrations up to 1.5 µM are usually reported in the general population. This study was primarily aimed to investigate changes of induced by sildenafil in a wide range of concentrations (0.1-100 µM). Additionally, the effect of combination of sildenafil and Ba at selected clinically-relevant concentrations was tested, at 0.1 µM both on and on the action potential duration (APD). Experiments were performed by the whole-cell patch-clamp technique on enzymatically isolated rat ventricular cardiomyocytes, mostly at 23°C with the exception of APD measurements which were performed at 37°C as well. Sildenafil caused a significant, reversible, and concentration-dependent inhibition of that did not differ at -50 and -110 mV. Simultaneous application of sildenafil and Ba at 0.1 µM revealed a massive inhibition of both inward and outward components of (this synergy was missing at other tested combinations). The combined effect at 0.1 µM (45.7 ± 5.7 and 43.0 ± 6.9% inhibition at -50 and -110 mV, respectively) was significantly higher than a simple sum of almost negligible effects of the individual substances and it led to a significant prolongation of APD at both 23 and 37°C. To our knowledge, similar potentiation of the drug-channel interaction has not been described. The observed massive inhibition of induced by a combined action of the vasodilator sildenafil and environmental contaminant Ba at a low concentration and resulting in a significant APD prolongation may contribute to the genesis of arrhythmias observed in some patients treated with sildenafil.