Abstract
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, Ba(2+) is used as a specific inhibitor of I (K1) at high concentrations (usually 100 µM). Being an environmental contaminant, it is also present in the human body; Ba(2+) plasmatic concentrations up to 1.5 µM 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 µM). Additionally, the effect of combination of sildenafil and Ba(2+) at selected clinically-relevant concentrations was tested, at 0.1 µM 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°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 I (K1) that did not differ at -50 and -110 mV. Simultaneous application of sildenafil and Ba(2+) at 0.1 µM 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 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 I (K1) induced by a combined action of the vasodilator sildenafil and environmental contaminant Ba(2+) 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.