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(Circulation. 2000;102:275.)
© 2000 American Heart Association, Inc.

Brief Rapid Communication

Sildenafil (Viagra) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current

Peter Geelen, MD, PhD; Benoit Drolet, MSc; Jimmy Rail, MSc; Jocelyn Bérubé, MSc; Pascal Daleau, PhD; Guy Rousseau, PhD; René Cardinal, PhD; Gilles E. O’Hara, MD; Jacques Turgeon, PhD

From the Institut de Cardiologie de Québec, Hôpital Laval (P.G., B.D., J.R., J.B., P.D., G.E.O., J.T.) et Facultés de Pharmacie (B.D., J.R., J.T.) et de Médecine (P.G., J.B., P.D., G.E.O., J.T.), Université Laval, Sainte-Foy, Québec; and Centre de Recherche, Hôpital du Sacré-Cur de Montréal (B.D., G.R., R.C., J.T.), Département de Pharmacologie, Faculté de Médecine (G.R., R.C., J.T.) et Faculté de Pharmacie (J.T.), Université de Montréal, Montréal, Québec, Canada.

Correspondence to Jacques Turgeon, PhD, Dean, Faculté de Pharmacie, University of Montreal, C.P. 6128 succursale Centre-ville, Montreal, Québec, Canada H3C 3J7. E-mail jacques.turgeon{at}umontreal.ca

Background—Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia.

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 µmol/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_Kr) of the delayed rectifier potassium current: activating current was 50% decreased at 100 µmol/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 III 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.

Key Words: proarrhythmia • I_Kr blockers • sildenafil

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