Methods and Results-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mu mol/L. Action potential duration increased 15% from baseline 117 +/- 3 to 134 +/- 2 ms with sildenafil during pacing 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 ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n = 30) demonstrated concentration-dependent block of the rapid component (I,) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mu mol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I-K-like current.

Conclusions-Sildenafil possesses direct cardiac electrophysiological effects similar to class In antiarrhythmic drugs. These effects are observed at concentrations 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.