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

Article

关键词: PIG VENTRICULAR MYOCYTES;    INHERITED CARDIAC-ARRHYTHMIA;    HUMAN ATRIAL MYOCYTES;    GUINEA-PIG;    EARLY AFTERDEPOLARIZATIONS;    2 COMPONENTS;    K+ CURRENT;    OUTWARD CURRENT;    I-KS;    KETOCONAZOLE;   

DOI  :  10.1161/01.CIR.97.2.204

来源: SCIE

【 摘 要 】

Background-Lengthening of the QT interval and torsades de pointes resulting in cardiac arrests and deaths have been noticed during treat ment 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 (IK5000). 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-Ks 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 (MAPD(90)). 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 mu mol/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-Ks by the drug was less potent (estimated IC50 > 10 mu mol/L). In isolated hearts (n=9 experiments), cisapride 100 nmol/L increased 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-Block of I-Kr gives an explanation to lengthening of cardiac repolarization observed in isolated guinea pig hearts. Potent block of I-Kr 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.

【 授权许可】

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