(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
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-C
ur 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
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Abstract |
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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 (IKr) 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 IK-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 • IKr blockers • sildenafil
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Introduction |
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The drug sildenafil citrate is a successful tool in the treatment of impotence through a selective inhibition of the phosphodiesterase V that inactivates cyclic guanine monophosphate (cGMP), the mediator of smooth muscle relaxation in the corpus cavernosum.1 2
As impotence is a common problem among patients with cardiac disease, sildenafil is increasingly prescribed by cardiologists.3 Several deaths have been reported in patients taking sildenafil, but it was generally assumed that they were related to an underlying disease (eg, ischemia) and not to a specific drug effect.3 4
We investigated whether unexpected electrophysiological effects of sildenafil on cardiac repolarization might provide an alternate explanation for an increased risk of sudden death. We therefore determined action potential–prolonging effects of sildenafil in isolated hearts and characterized the effects of the drug on IKr using the patch-clamp technique.
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Methods |
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Experiments were performed in accordance with our institutional guidelines on animal use in research. Animals were housed and maintained in compliance with the Guide to the Care and Use of Experimental Animals of the Canadian Council on Animal Care.
Experiments With Isolated Hearts
Experiments with isolated guinea pig hearts were performed as
described previously.5 The hearts were perfused with
Krebs-Henseleit buffer during a control period of 10 minutes, followed
by 15 minutes with buffer containing 30 µmol/L of sildenafil
dissolved in 100 µL of dimethylsulfoxide (DMSO). Perfusion with
buffer containing no drug was then restarted during a 10-minute washout
period. Monophasic action potentials from the left ventricle were
recorded every 60 seconds for brief periods of 3 seconds, at
basic pacing cycle lengths (BCL) of 250, 200, and 150 ms.
Patch-Clamp Experiments
Experiments were performed on human
ether-a-go-go–related gene (HERG)–transfected HEK293
cells. Preparation and harvesting of the HEK293 cells were done as
described by Zhou et al.6 Membrane currents were
recorded in whole cell configuration using suction pipettes. The
composition of superfusion and internal pipette solutions were
described by Zhou et al.6 Sildenafil solutions of 1 to
100 µmol/L were prepared daily by dissolving required amounts of
the drug in 100 µL of DMSO. The same volume of DMSO was added in
baseline and washout buffer solutions. HERG gene was also transiently
transfected in CHO cells as described by Bérubé et
al.7 Recordings of currents and composition of
superfusion and internal pipette solutions were described by
Bérubé et al.7 All voltage-clamp experiments
were performed at 22°C to 23°C.
Statistical Analysis
Data are presented as means±SEM. Isolated heart data on
the magnitude of sildenafil effects were analyzed with a
student’s paired t test. In the patch-clamp experiments,
concentration-dependent block of HERG activating current was tested by
Hotelling’s T2 test. A
P value <0.05 was considered statistically significant.
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Results |
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Experiments With Isolated Hearts
Examples of monophasic action potentials recorded at baseline and during perfusion with sildenafil 30 µmol/L at a BCL of 250 ms are illustrated in Figure 1A
.
Experiments in isolated hearts (n=10) showed an increase in monophasic
action potential duration measured at 90% repolarization
(MAPD90) during perfusion with sildenafil 30
µmol/L (Figure 1B): At a BCL of 250 ms,
MAPD90 increased from 117±3 ms at baseline to
134±2 ms after 15 minutes of drug perfusion (P<0.05),
decreasing back to 126±4 ms after 10 minutes of washout
(P<0.05 versus sildenafil). At the shortest BCL of 150 ms,
MAPD90 increased from 99±2 at baseline to 105±2
ms after sildenafil perfusion (P<0.05), returning to
baseline after washout (99±2 ms). Thus, sildenafil was associated with
a 15% increase in MAPD90 at the longest BCL and
with a 6% increase at the shortest BCL. Such reverse use-dependent
characteristics are typically seen with IKr
blockers.
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Patch-Clamp Experiments
The mechanism of the action potential-prolonging effect of
sildenafil was elucidated by the patch-clamp experiments in HEK293 and
in CHO cells. Figure 2A shows currents
elicited in a HERG-transfected HEK293 cell perfused under control
conditions, after 15 minutes of sildenafil 30 µmol/L and after
20 minutes of washout. In this cell, sildenafil 30 µmol/L caused
a 
40% reduction of the activating current, whereas the reduction of
the tail current was 25%.
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To ascertain that the effects of sildenafil were not due to a
modulation of a HEK293 cell endogenous current, we
confirmed the inhibitory effects of sildenafil in
HERG-transfected CHO cells, which exhibit no
IK-like endogenous
currents.8 Figure 2B
shows currents elicited in a
HERG-transfected CHO cell perfused under control conditions, after 15
minutes of sildenafil 30 µmol/L and after 20 minutes of washout.
In this cell, sildenafil 30 µmol/L caused a 50% reduction of
the activating current, and a 44% reduction of the tail current.
Sildenafil 30 µmol/L had no effect on HERG channel activation,
deactivation, or inactivation kinetics.
In HERG-transfected HEK293 cells, block of activating currents
was assessed with sildenafil concentrations ranging from 1 to 100
µmol/L and the data were fitted to the Hill equation, giving an
estimated IC50 of 100 µmol/L (Figure 2C).
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Discussion |
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Our results indicate that sildenafil can prolong cardiac repolarization by blocking IKr. In fact, we have shown that sildenafil 30 µmol/L caused a clinically relevant 15% prolongation of cardiac repolarization, which is comparable with the effect of cisapride 100 nmol/L under the same conditions.5 It has been shown that IKr block may lead to triggered ventricular arrhythmias and sudden death.9 These results provide a new potential explanation for sudden death during sildenafil treatment.
Inhibition of HERG current was demonstrated in both HEK293 and CHO cell lines. In HEK293 cells, the estimated IC50 for IKr was 100 µmol/L. Plasma concentrations of sildenafil after treatment with single doses of 25 to 100 mg are around 1 µmol/L.10 Because sildenafil is a strong lipophilic drug, relevant tissue concentrations are probably higher. However, based on our results, several-fold higher plasma concentrations than these encountered in clinical practice would be required before significant IKr block occurred. Drug metabolism studies have demonstrated that CYP3As are the principal enzymes involved in the biotransformation of sildenafil.10 Thus, one could expect an important rise in sildenafil plasma levels when it is coadministered with CYP3A inhibitors (macrolides, imidazoles) or other CYP3A substrates (many cardiac drugs, such as calcium antagonists and statins). Indeed, a 20-fold increase in cisapride plasma concentrations (another inadvertent IKr blocker that is a CYP3A4 substrate) was reported during coadministation with fluconazole and erythromycin.11
The cardiovascular effects of sildenafil in randomized, controlled clinical trials were minor, although patients with underlying heart disease were generally excluded from these studies.1 10 12 From April 1998 through mid-November 1998, the FDA has been able to document 130 cases of death in US patients using sildenafil. Sixty-two percent of them died of cardiovascular events (mostly myocardial infarction or cardiac arrest), whereas the cause of death was unmentioned or unknown for 37% of patients.10 Therefore, care should be taken when prescribing sildenafil to patients with cardiac disease.4 Care should also be taken with patients at risk for impaired drug elimination and is further emphasized by these new findings. Because sildenafil can block IKr, caution is also needed during coadministration with other IKr blockers such as class III drugs and other compounds such as erythromycin, antihistamines, and cisapride.5 13 14 Moreover, the present findings with sildenafil should also remind the whole concern of acquired long QT syndrome as a "drug-revealed" form of silent congenital long QT syndrome, observable under the effect of a growing list of drugs.
Conclusions
Sildenafil blocks IKr and prolongs cardiac
repolarization at concentrations that may be seen after drug overdose
or in the presence of impaired drug elimination. Clinical attention to
QT prolongation and triggered ventricular
tachyarrhythmias is warranted in patients with hepatic
or renal insufficiency or suffering from the long QT syndrome and in
patients on multi-drug regimens.
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Acknowledgments |
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Dr Geelen was the recipient of a postdoctoral fellowship from the Heart and Stroke Foundation of Canada. Benoit Drolet is the recipient of studentships from the Heart and Stroke Foundation of Canada and from the Fonds pour la Formation de Chercheurs et l’Aide à la Recherche (FCAR). Jimmy Rail was the recipient of a studentship from the Quebec Heart Institute. Dr Daleau is the recipient of a scholarship from the Fonds de la Recherche en Santé du Québec (FRSQ). Dr Rousseau is the recipient of a scholarship from the MRC/Canadian Hypertension Society. Dr Turgeon was the recipient of a scholarship from the Joseph C. Edwards Foundation. The authors also thank Michel Blouin and Lynn Atton for technical assistance. This work was presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, November 1999. Supported by Medical Research Council of Canada (MT-11876) (to J.T.) and Heart and Stroke Foundation of Quebec.
Received April 5, 2000; revision received May 25, 2000; accepted May 25, 2000.
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References |
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1. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397–1404.
2. Chuang AT, Strauss JD, Murphy RA, et al. Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro. J Urol. 1998;160:257–261.[Medline] [Order article via Infotrieve]
3. Conti CR. Viagra®, the latest cardio-vascular drug. Clin Cardiol. 1998;21:616. Comment.[Medline] [Order article via Infotrieve]
4.
Cheitlin MD, Hutter AM, Brindis RG, et al. Use of
sildenafil (Viagra) in patients with cardiovascular
disease. Circulation. 1999;99:168–177.
5.
Drolet B, Khalifa M, Daleau P, et al. Block of the
rapid component of the delayed rectifier potassium current by the
prokinetic agent cisapride underlies drug-related lengthening of the QT
interval. Circulation. 1998;97:204–210.
6. Zhou Z, Gong Q, Ye B, et al. Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J. 1998;74:230–241.[Medline] [Order article via Infotrieve]
7. Bérubé J, Chahine M, Daleau P. Modulation of HERG potassium channel properties by external pH. Pflügers Arch. 1999;438:419–422.[Medline] [Order article via Infotrieve]
8. Yu SP, Kerchner GA. Endogenous voltage-gated potassium channels in human embryonic kidney (HEK293) cells. J Neurosci Res. 1998;52:612–617.[Medline] [Order article via Infotrieve]
9. Priori SG. Exploring the hidden danger of noncardiac drugs. J Cardiovasc Electrophysiol. 1998;9:1114–1116.[Medline] [Order article via Infotrieve]
10. Zusman RM, Morales A, Glasser DB, et al. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol. 1999;83:35C–44C.[Medline] [Order article via Infotrieve]
11. Pettignano R, Chambliss R, Darsey E, Heard M, Clark R. Cisapride-induced dysrhythmia in a pediatric patient receiving extracorporeal life support. Crit Care Med. 1996;24:1268–1271.[Medline] [Order article via Infotrieve]
12. Morales A, Gingell C, Collins M, et al. Clinical safety of oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res. 1998;10:69–73.[Medline] [Order article via Infotrieve]
13.
Daleau P, Lessard E, Groleau MF, et al. Erythromycin
blocks the rapid component of the delayed rectifier potassium current
and lengthens repolarization of guinea pig ventricular
myocytes. Circulation. 1995;91:3010–3016.
14.
Salata JJ, Jurkiewicz NK, Wallace AA, et al. Cardiac
electrophysiological actions of the
histamine H1-receptor antagonists astemizole and
terfenadine compared with chlorpheniramine and pyrilamine. Circ
Res. 1995;76:110–119.
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