Zhang Z H, Boutjdir M, el-Sherif N
Cardiology Division, State University of New York, Brooklyn.
Circ Res. 1994 Oct;75(4):711-21. doi: 10.1161/01.res.75.4.711.
Ketanserin (KT), an antihypertensive agent, has been shown to prolong action potential duration (APD) and QT interval and to induce torsade de pointes in some patients. We previously suggested that the prolongation of APD could be due to KT inhibition of the fast component of the delayed rectifier current (IKr) in guinea-pig myocytes. However, in other tissue such as human atrium, Purkinje fibers, epicardial cells, and rat ventricular myocytes, the transient outward potassium current (Ito) is one of the major repolarizing currents. We investigated the possibility that KT could also increase APD by blocking Ito. Action potentials and membrane currents were recorded from rat ventricular myocytes known to have a large Ito by using whole-cell patch-clamp techniques. We found that KT (50 mumol/L) significantly prolonged APD at 50% repolarization by 218% (P < .05) and APD at 90% repolarization by 256% (P < .05) with no significant effect on other action potential parameters. Time-dependent Ito and sustained current (ISus) were measured in the presence of 400 nmol/L nisoldipine during depolarizing pulses to 40 mV from a holding potential of -100 mV every 10 seconds. KT resulted in a concentration- and time-dependent inhibition of charge area of Ito evaluated by integration with an EC50 of 8.3 mumol/L. The inhibitory effect of KT (10 mumol/L) was seen at voltages from 0 to 80 mV without any shift of the current-voltage relation of peak Ito. KT did not significantly change activation, inactivation, and reactivating curves of Ito. Kinetic analysis of Ito showed a biexponential fit of inactivation in 80.5% of total tracings studied at voltages between -30 and 80 mV (n = 149, R = .99 +/- .01). The inhibitory effect of KT was more prominent on charge areas of the slow component (Qs) than the fast component (Qf) of Ito (Qf = 33.2 +/- 6.2 s.pA and Qs = 235.5 +/- 7.4 s.pA for the control condition; 12.4 +/- 4.3 and 59.6 +/- 17 s.pA for KT at 40 mV; n = 4). The binding association (k) and dissociation (l) constants at 40 mV were 9.0 +/- 0.9x10(6) M-1.s-1 and 86.6 +/- 0.3 s-1, respectively. KT also blocked ISus in a dose-dependent manner with an EC50 of 11.2 mumol/L and had no significant effect on both the inward rectifier potassium current and the L-type calcium current.(ABSTRACT TRUNCATED AT 400 WORDS)
酮色林（KT）是一种抗高血压药物，已被证明可延长动作电位时程（APD）和QT间期，并在一些患者中诱发尖端扭转型室速。我们之前认为，APD的延长可能是由于KT抑制了豚鼠心肌细胞中延迟整流钾电流（IKr）的快速成分。然而，在其他组织如人的心房、浦肯野纤维、心外膜细胞和大鼠心室肌细胞中，瞬时外向钾电流（Ito）是主要的复极电流之一。我们研究了KT是否也可能通过阻断Ito来增加APD。采用全细胞膜片钳技术，从已知具有较大Ito的大鼠心室肌细胞记录动作电位和膜电流。我们发现，KT（50 μmol/L）使50%复极化时的APD显著延长218%（P <.05），90%复极化时的APD显著延长256%（P <.05），而对其他动作电位参数无显著影响。在从-100 mV的静息电位每10秒去极化至40 mV的脉冲过程中，在存在400 nmol/L尼索地平的情况下测量时间依赖性Ito和持续电流（ISus）。KT导致Ito电荷面积的浓度和时间依赖性抑制，通过积分评估其半数有效浓度（EC50）为8.3 μmol/L。在0至80 mV的电压下可见KT（10 μmol/L）的抑制作用，且Ito峰值的电流-电压关系无任何偏移。KT对Ito的激活、失活和再激活曲线无显著影响。Ito的动力学分析显示，在-30至80 mV的电压下，80.5%的总记录曲线中失活呈双指数拟合（n = 149，R =.99 ±.01）。KT对Ito慢成分（Qs）电荷面积的抑制作用比对快成分（Qf）更显著（对照条件下Qf = 33.2 ± 6.2 s.pA，Qs = 235.5 ± 7.4 s.pA；40 mV时KT作用下分别为12.4 ± 4.3和59.6 ± 17 s.pA；n = 4）。40 mV时的结合常数（k）和解离常数（l）分别为9.0 ± 0.9×10⁶ M⁻¹·s⁻¹和86.6 ± 0.3 s⁻¹。KT还以剂量依赖性方式阻断ISus，EC50为11.2 μmol/L，对内向整流钾电流和L型钙电流均无显著影响。（摘要截短于400字）
