Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval

Abstract

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 (I(Kr)) and slow (I(Ks)) components of the delayed rectifier current (I(K)) 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, I(Kr) and I(Ks), 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 (I(K250)) or 5000 ms (I(K5000)). Effects of cisapride on the I(Kr) component were assessed by measurement of time-dependent activating currents elicited by short pulses (250 ms; I(K250)) to low depolarizing potentials (-20, -10, and 0 mV). Time- dependent activating currents elicited by long pulses (5000 ms; I(K5000)) to positive potentials (>+30 mV) were recorded to assess effects of the drug on the I(K5) 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 I(Kr), the major time-dependent outward current elicited by short pulses (I(K250)) 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 I(K5) 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