Sildenafil (viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current

Background-Several cases of unexpected death have been reported with silden afil in patients predisposed to ischemic cardiac events. Although acute epi sodes of ischemia could account for some of these deaths, we hypothesized t hat sildenafil may have unsuspected electrophysiological effects predisposi ng some patients to proarrhythmia. Methods and Results-Studies were undertaken in 10 isolated guinea pig heart s that demonstrated prolongation of cardiac repolarization in a reverse use -dependent manner by sildenafil 30 mu mol/L. Action potential duration incr eased 15% from baseline 117 +/- 3 to 134 +/- 2 ms with sildenafil during pa cing at 250 ms cycle length, whereas a 6% increase from 99 +/- 2 to 105 +/- 2 ms was seen with pacing at 150 ms cycle length. Experiments in human eth er-a-go-go-related gene (HERG)-transfected HEK293 cells (n = 30) demonstrat ed concentration-dependent block of the rapid component (I,) of the delayed rectifier potassium current: activating current was 50% decreased at 100 m u mol/L. This effect was confirmed using HERG-transfected Chinese hamster o vary (CHO) cells, which exhibit no endogenous I-K-like current. Conclusions-Sildenafil possesses direct cardiac electrophysiological effect s similar to class In antiarrhythmic drugs. These effects are observed at c oncentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.