Combination of Sildenafil and Ba2+ 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 I-K1 are known to contribute to the pathogenesis of fibrillation, the effect of sildenafil on I-K1 has not been studied. In experiments, Ba2+ is used as a specific inhibitor of I-K1 at high concentrations (usually 100 mu M). Being an environmental contaminant, it is also present in the human body; Ba2+ plasmatic concentrations up to 1.5 mu M are usually reported in the general population. This study was primarily aimed to investigate changes of I-K1 induced by sildenafil in a wide range of concentrations (0.1-100 mu M). Additionally, the effect of combination of sildenafil and Ba2+ at selected clinically-relevant concentrations was tested, at 0.1 mu M both on I-K1 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 degrees C with the exception of APD measurements which were performed at 37 degrees C as well. Sildenafil caused a significant, reversible, and concentration-dependent inhibition of I-K1 that did not differ at -50 and -110 mV. Simultaneous application of sildenafil and Ba2+ at 0.1 mu M revealed a massive inhibition of both inward and outward components of I-K1 (this synergy was missing at other tested combinations). The combined effect at 0.1 mu M (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 degrees C. To our knowledge, similar potentiation of the drug-channel interaction has not been described. The observed massive inhibition of I-K1 induced by a combined action of the vasodilator sildenafil and environmental contaminant Ba2+ 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.