BLOCK OF THE RAPID COMPONENT OF THE DELAYED RECTIFIER POTASSIUM CURRENT BY THE PROKINETIC AGENT CISAPRIDE UNDERLIES DRUG-RELATED LENGTHENING OF THE QT INTERVAL

Background-Lengthening of the QT interval and torsades de pointes resu lting in cardiac arrests and deaths have been noticed during treat men t 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-relate d toxicity because of their role in repolarization of cardiac ventricu lar myocytes. Our objectives were to (1) characterize effects of cisap ride on two major time-dependent outward potassium currents involved i n the repolarization of cardiac ventricular myocytes, I-Kr and I-Ks, a nd (2) determine action potential-prolonging effects of cisapride on i solated hearts. Methods and Results-A first set of experiments was per formed 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 p ulses lasting either 250 ms (I-K250) or 5000 ms (IK5000). Effects of c isapride on the I-Kr component were assessed by measurement of time-de pendent activating currents elicited by short pulses (250 ms; I-K250) to low depolarizing potentials (-20, -10, and 0 mV). Time-dependent ac tivating currents elicited by long pulses (5000 ms; I-K5000) to positi ve potentials (>+30 mV) were recorded to assess effects of the drug on the I-Ks component. A second set of experiments was conducted in isol ated guinea pig hearts buffer-perfused in the Langendorff mode to asse ss effects of the drug on monophasic action potential duration measure d at 90% repolarization (MAPD(90)). Hearts were exposed to cisapride 1 00 nmol/L at decremental pacing cycle lengths of 250, 225, 200, 175, a nd 150 ms to determine reverse frequency-dependent effects of the drug . Overall, 112 myocytes were exposed to seven concentrations of cisapr ide (10 nmol/L to 10 mu mol/L). Cisapride inhibited I-Kr, the major ti me-dependent outward current elicited by short pulses (I-K250) to low depolarizing potentials, in a concentration-dependent manner with an I C50 of 15 nmol/L (therapeutic levels, 50 to 200 nmol/L). Conversely, b lock of I-Ks by the drug was less potent (estimated IC50 > 10 mu mol/L ). In isolated hearts (n=9 experiments), cisapride 100 nmol/L increase d MAPD(90) 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-B lock of I-Kr gives an explanation to lengthening of cardiac repolariza tion observed in isolated guinea pig hearts. Potent block of I-Kr is a lso likely to underlie prolongation of the QT interval observed in pat ients receiving clinically recommended doses of cisapride as well as s evere cardiac toxicity (torsades de pointes) observed in patients with increased plasma concentrations of the drug.