Yuill K H, Convery M K, Dooley P C, Doggrell S A, Hancox J C
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol, BS8 1TD.
Br J Pharmacol. 2000 Aug;130(8):1753-66. doi: 10.1038/sj.bjp.0703476.
BDF 9198 (a congener of DPI 201 - 106 and BDF 9148) was found to be a positive inotrope on guinea-pig isolated ventricular muscle strips. The effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes were studied using the whole cell patch clamp method. In normal external solution, at 37 degrees C, action potential duration at 50% repolarization (APD(50)) was 167.4+/-8.36 ms (n=37). BDF 9198 produced a concentration-dependent increase in APD(50) (no significant increase at 1x10(-10) M; and APD(50) values of 273.03+/-35.8 ms at 1x10(-9) M; n=6, P<0.01 and 694.7+/-86.3 ms at 1x10(-7) M; P<0.001, n=7). At higher concentrations in the range tested, BDF 9198 also induced early and delayed and after-depolarizations. Qualitative measurements of I(Na) with physiological Na showed prolongation of the current by BDF 9198, and the appearance of transient oscillatory inward currents at high concentrations. Quantitative recording conditions for I(Na) were established using low external [Na] and by making measurements at room temperature. The current - voltage relation, activation parameters and time-course of I(Na) were similar before and after a partial blocking dose of Tetrodotoxin (TTX, 1 microM), despite a 2 fold difference in current amplitude. This suggests that voltage-clamp during flow of I(Na) was adequately maintained under our conditions. Selective measurements of I(Na) at room temperature showed that BDF 9198 induced a concentration-dependent, sustained component of I(Na) (I(Late)) and caused a slight left-ward shift in the current - voltage relation for peak current. The drug-induced I(Late) showed a similar voltage dependence to peak current in the presence of BDF 9198. Both peak current and I(Late) were abolished by 30 microM TTX and were sensitive to external [Na]. Inactivation of control I(Na) during a 200 ms test pulse to -30 mV followed a bi-exponential time-course. In addition to inducing a sustained current component, BDF 9198 left the magnitude of the fast inactivation time-constant unchanged, but increased the magnitude of the slow inactivation time-constant. Additional experiments with a longer pulse (1 s) raised the possibility that in the presence of BDF 9198, I(Na) inactivation may be comprised of more than two phases. No significant effects of 1x10(-6) M BDF 9198 were observed on the L-type calcium current, or delayed and inward rectifying potassium currents measured at 37 degrees C. It is concluded that the prolongation of APD(50) by BDF 9198 resulted from selective modulation of I(Na). Reduced current inactivation induced a persistent I(Na), increasing the net depolarizing current during the action potential. This action of the drug indicates a potential for 'QT prolongation' of the ECG. The observation of after-depolarizations suggests a potential for proarrhythmia at some drug concentrations.
BDF 9198（DPI 201 - 106和BDF 9148的同系物）被发现对豚鼠离体心室肌条具有正性肌力作用。采用全细胞膜片钳方法研究了BDF 9198对豚鼠离体心室肌细胞动作电位和离子电流的影响。在正常外部溶液中，37℃时，50%复极化时的动作电位时程（APD(50)）为167.4±8.36毫秒（n = 37）。BDF 9198使APD(50)呈浓度依赖性增加（1×10⁻¹⁰ M时无显著增加；1×10⁻⁹ M时APD(50)值为273.03±35.8毫秒；n = 6，P < 0.01；1×10⁻⁷ M时为694.7±86.3毫秒；P < 0.001，n = 7）。在测试的较高浓度范围内，BDF 9198还诱导早期、延迟和后去极化。用生理Na对I(Na)进行定性测量显示，BDF 9198使电流延长，且在高浓度时出现短暂振荡内向电流。使用低外部[Na]并在室温下进行测量，建立了I(Na)的定量记录条件。尽管电流幅度相差2倍，但在给予部分阻断剂量的河豚毒素（TTX，1微摩尔）前后，I(Na)的电流 - 电压关系、激活参数和时间进程相似。这表明在我们的条件下，I(Na)流动期间的电压钳制得到了充分维持。在室温下对I(Na)进行选择性测量显示，BDF 9198诱导I(Na)产生浓度依赖性的持续成分（I(Late)），并使峰值电流的电流 - 电压关系略有左移。在存在BDF 9198的情况下，药物诱导的I(Late)对峰值电流表现出相似的电压依赖性。峰值电流和I(Late)均被30微摩尔TTX消除，且对外部[Na]敏感。在向 - 30 mV进行200毫秒测试脉冲期间，对照I(Na)的失活遵循双指数时间进程。除了诱导持续电流成分外，BDF 9198使快速失活时间常数的大小保持不变，但增加了缓慢失活时间常数的大小。用更长脉冲（1秒）进行的额外实验增加了这样一种可能性，即在存在BDF 9198的情况下，I(Na)失活可能由两个以上阶段组成。在37℃下，未观察到1×10⁻⁶ M BDF 9198对L型钙电流或延迟和内向整流钾电流有显著影响。结论是，BDF 9198使APD(50)延长是由I(Na)的选择性调节所致。电流失活减少诱导了持续性I(Na)，增加了动作电位期间的净去极化电流。该药物的这一作用表明心电图有“QT延长”的可能性。后去极化的观察结果表明在某些药物浓度下有致心律失常的可能性。
