摘要
为观察bepridi1对豚鼠单心室肌细胞动作电位时程 (APD)及动作电位形成过程中主要离子流的作用 ,探讨其诱发长QT间期及多形性室性心动过速的电生理机制。采用Nystatin 破膜法研究bepridil对豚鼠单心室肌细胞APD的作用 ,常规全细胞方法研究其对主要跨膜离子流的作用。结果 :在 5Hz剌激频率时 ,0 .1μmol/Lbepridil使APD明显延长 ,APD90 平均延长 18.0l%( 6 2 .40± 7.6 5msvs 5 2 .88± 5 .90ms,P <0 .0 5 )。当bepridil在细胞外液中的浓度增至1或 3μmol/L时 ,APD恢复到用药前水平 ;但当药物浓度进一步提高到 10 μmol/L时 ,APD明显缩短 ,动作电位幅度下降 ,这一作用随着药物浓度的升高而加强。在持续 2 5 0ms和 10 0 0ms至不同膜电位的去极化的实验中 ,bepridil能明显降低延迟整流钾电流 (IK)的尾电流和稳态电流 ,抑制作用呈浓度依赖性。在 3 0 0 0ms、+6 0mV去极化及IK的快成分 (Ikr)被E 40 31完全阻断时 ,bepridil对IK 的慢成分 (Iks)亦具有抑制作用 ,但两种情况下的半抑制浓度 (IC50 )不同 :3 0 0 0ms,+6 0mV去极化bepridil对IK 的IC50 为 1.6 2 μmol/L ,约为在 +2 0mV、10 0 0ms去极化时对IK 尾电流IC50 ( 0 .12 μmol/L)的 13.5倍。在 1Hz频率去极化时 ,该药对钠电流 (INa)和钙电流 (ICa)
By observing the effects of bepridil on action potential duration (APD) and main currents involved in the depolarization and repolarization of isolated guinea pig ventricular myocytes,we try to understand the mechanisms of QT prolongation and polymorphic ventricular arrhythmias induced by the drug.Nystatin-prefortated configuration and the conventional whole-cell configuration of the patch-clamp techniques were used.Results:At a stimulation frequency of 5 Hz,0.1 μmol/L bepridil prolonged APD 90 by 18.01% (P<0.05),but 1 μmol/L and 3 μmol/L bepridil did not change APD compared with that of the control;while 10 μmol/L and 30 μmol/L bepridil not only shortened APD,but also decreased the amplitude of action potential.Bepridil decreased both the delayed rectifier K + current (I K) tail current and I k steady state current elicited by 250 msec,1 000 msec,and 3 000 msec duration of pulses depolarized to different membrane potentials,and the blockade was dose-dependent.It also decreased the slowly activating component of I k(I ks) after the rapidly activating components of I k(I kr) was blocked by E-4031,but the IC 50 were different,i.e.,IC 50 for blocking Iks was thirteen times larger than the IC 50 for blocking I k at 1 000 msec,+20 mV depolarization.Effects of bepridil on I Na and I Ca were also dose-dependentt,the IC 50 were 1.61 μmol/L and 1.87 μmol/L separately,almost the same as that of bepridil on I ks.Conclusion:Bepridil blocked both I kr and I ks.At low concentration,it mainly block the I kr;while at higher concentration,it also blocked I ks,I Na,I Ca.
