From Quebec Heart Institute, Laval Hospital, Faculty of Pharmacy (B.D.,
M.K., B.A.H., J.T.) and Faculty of Medicine (P.D., J.T.), Laval University,
Ste-Foy, Quebec, Canada, G1V 4G5.
Correspondence to Jacques Turgeon, PhD, Centre de recherche, Hôpital Laval, 2725 chemin Ste-Foy, Ste-Foy, Québec, Canada, G1V 4G5. E-mail phajtu{at}hermes.ulaval.ca
Background—Lengthening of the QT
interval and torsades de pointes resulting in cardiac arrests and
deaths have been noticed during treatment with cisapride, a newly
developed gastrointestinal prokinetic agent. The rapid
(IKr) and slow
(IKs) components of the delayed rectifier
current (IK) are candidate ionic currents to
explain cisapride-related toxicity because of their role in
repolarization of cardiac ventricular myocytes. Our
objectives were to (1) characterize effects of cisapride on two major
time-dependent outward potassium currents involved in the
repolarization of cardiac ventricular myocytes,
IKr and IKs, and
(2) determine action potential–prolonging effects of cisapride on
isolated hearts.
Methods and Results—A first set of experiments was performed in
isolated guinea pig ventricular myocytes with the
whole-cell configuration of the patch-clamp technique. Cells were held
at -40 mV while time-dependent outward currents were elicited by
depolarizing pulses lasting either 250 ms
(IK250) or 5000 ms
(IK5000). Effects of cisapride on the
IKr component were assessed by measurement
of time-dependent activating currents elicited by short pulses (250 ms;
IK250) to low depolarizing potentials (-20,
-10, and 0 mV). Time-dependent activating currents elicited by long
pulses (5000 ms; IK5000) to positive
potentials (>+30 mV) were recorded to assess effects of the drug
on the IKs component. A second set of
experiments was conducted in isolated guinea pig hearts buffer-perfused
in the Langendorff mode to assess effects of the drug on monophasic
action potential duration measured at 90% repolarization
(MAPD90). Hearts were exposed to cisapride 100 nmol/L at
decremental pacing cycle lengths of 250, 225, 200, 175, and 150 ms to
determine reverse frequency-dependent effects of the drug. Overall, 112
myocytes were exposed to seven concentrations of cisapride (10 nmol/L
to 10 µmol/L). Cisapride inhibited
IKr, the major time-dependent outward
current elicited by short pulses (IK250) to
low depolarizing potentials, in a concentration-dependent manner with
an IC50 of 15 nmol/L (therapeutic levels, 50 to 200
nmol/L). Conversely, block of IKs by the
drug was less potent (estimated IC50 >10 µmol/L).
In isolated hearts (n=9 experiments), cisapride 100 nmol/L increased
MAPD90 by 23±3 (P<.05) at a basic cycle
length of 250 ms but by only 7±1 ms (P<.05) at a basic
cycle length of 150 ms.
Conclusions—Block of IKr gives an
explanation to lengthening of cardiac repolarization observed in
isolated guinea pig hearts. Potent block of
IKr is also likely to underlie prolongation
of the QT interval observed in patients receiving clinically
recommended doses of cisapride as well as severe cardiac toxicity
(torsades de pointes) observed in patients with increased plasma
concentrations of the drug.
© 1998 American Heart Association, Inc.
Basic Science Reports
Block of the Rapid Component of the Delayed Rectifier Potassium Current by the Prokinetic Agent Cisapride Underlies Drug-Related Lengthening of the QT Interval
Key Words: electrophysiology • cisapride • torsade de pointes
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