Baláti B, Iost N, Simon J, Varró A, Papp J G
Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical University and Research Unit for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12, P.O. Box 427, H-6701, Szeged, Hungary.
Gen Pharmacol. 2000 Feb;34(2):85-93. doi: 10.1016/s0306-3623(00)00048-3.
The aim of the study was to determine the in vitro rate-dependent cellular electrophysiological effects of ambasilide (10 and 20 microM/l), a new investigational antiarrhythmic agent, in canine isolated ventricular muscle and Purkinje fibers by applying the standard microelectrode technique. At the cycle length (CL) of 1000 ms, ambasilide significantly prolonged the action potential duration measured at 90% repolarization (APD(90)) in both ventricular muscle and Purkinje fibers. Ambasilide (10 microM/l) produced a more marked prolongation of APD(90) at lower stimulation frequencies in Purkinje fibers (at CL of 2000 ms = 56.0 +/- 16.1%, n = 6, versus CL of 400 ms = 15.1 +/- 3.7%, n = 6; p < 0.05), but, in 20 microM/l, this effect was considerably diminished (15.2 +/- 3.6%, n = 6, versus 7.3 +/- 5.1%, n = 6, p < 0.05). In ventricular muscle, however, both concentrations of the drug induced an almost frequency-independent lengthening of APD(90) in response to a slowing of the stimulation rate (in 20 microM/l at CL of 5000 ms = 19.0 +/- 1.5%, n = 9, versus CL of 400 ms = 16.9 +/- 1.4%, n = 9). Ambasilide induced a marked rate-dependent depression of the maximal rate of rise of the action potential upstroke (V(max)) (in 20 microM/l at CL of 300 ms = -45.1 +/- 3.9%, n = 6, versus CL of 5000 ms = -8.5 +/- 3.9%, n = 6, p < 0. 05, in ventricular muscle) and the corresponding recovery of V(max) time constant was tau = 1082.5 +/- 205.1 ms (n = 6). These data suggest that ambasilide, in addition to its Class III antiarrhythmic action, which is presumably due to its inhibitory effect on the delayed rectifier potassium current, possesses I/B type antiarrhythmic properties as a result of the inhibition of the fast sodium channels at high frequency rate with relatively fast kinetics. This latter effect may play an important role in its known less-pronounced proarrhythmic ("torsadogenic") potential.
本研究的目的是通过应用标准微电极技术，确定新型抗心律失常药物安巴西利德（10和20微摩尔/升）在犬离体心室肌和浦肯野纤维中的体外频率依赖性细胞电生理效应。在1000毫秒的心动周期长度（CL）下，安巴西利德显著延长了心室肌和浦肯野纤维在90%复极化时测量的动作电位持续时间（APD(90)）。安巴西利德（10微摩尔/升）在较低刺激频率下使浦肯野纤维的APD(90)延长更为显著（在CL为2000毫秒时为56.0±16.1%，n = 6，而在CL为400毫秒时为15.1±3.7%，n = 6；p < 0.05），但在20微摩尔/升时，这种效应显著减弱（分别为15.2±3.6%，n = 6和7.3±5.1%，n = 6，p < 0.05）。然而，在心室肌中，两种浓度的药物在刺激频率减慢时均诱导APD(90)几乎与频率无关的延长（在20微摩尔/升时，CL为5000毫秒时为19.0±1.5%，n = 9，而CL为400毫秒时为16.9±1.4%，n = 9）。安巴西利德诱导动作电位上升最大速率（V(max)）明显的频率依赖性降低（在心室肌中，20微摩尔/升时，CL为300毫秒时为-45.1±3.9%，n = 6，而CL为5000毫秒时为-8.5±3.9%，n = 6，p < 0.05），V(max)的相应恢复时间常数为tau = 1082.5±205.1毫秒（n = 6）。这些数据表明，安巴西利德除了其III类抗心律失常作用（可能是由于其对延迟整流钾电流的抑制作用）外，由于在高频时以相对快速的动力学抑制快速钠通道，还具有I/B型抗心律失常特性。后一种效应可能在其已知的不太明显的促心律失常（“扭转型室速”）潜力中起重要作用。
