González Teresa, Arias Cristina, Caballero Ricardo, Moreno Ignacio, Delpón Eva, Tamargo Juan, Valenzuela Carmen
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
Br J Pharmacol. 2002 Dec;137(8):1269-79. doi: 10.1038/sj.bjp.0704978.
1 Levobupivacaine and ropivacaine are the pure S(-) enantiomers of N-butyl- and N-propyl-2',6'-pipecoloxylidide, developed as less cardiotoxic alternatives to bupivacaine. In the present study, we have analysed the effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels stably expressed in CHO cells. 2 The three drugs blocked HERG channels in a concentration-, time- and state-dependent manner. Block measured at the end of 5 s pulses to -10 mV induced by 20 microM bupivacaine (52.7+/-2.0%, n=15) and ropivacaine (55.5+/-2.7%, n=13) was similar (P>0.05) and both lower than that induced by levobupivacaine (67.5+/-4.2%, n=11) (P<0.05). 3 Dextrobupivacaine (20 microM) was less potent (47.2+/-5.2%, n=10) than levobupivacaine (P<0.05), indicating stereoselective HERG channel block. 4. Block induced by the three local anaesthetics exhibited a steep voltage dependence in the range of channel activation. In all cases, block measured at the maximum peak current at a test potential of 0 mV after promoting recovery from inactivation (I-->O) was lower than that observed at the end of 5-s pulses (I+O). 5. Levobupivacaine, ropivacaine and bupivacaine accelerated HERG inactivation kinetics, slowed the recovery from inactivation and shifted the inactivation curve towards more negative membrane potentials. The three local anaesthetics induced a rapid time-dependent decline after using a protocol that quickly activates HERG channels. 6. All these results suggest that: (1) these drugs bind to the open and the inactivated states of HERG channels, (2) they stabilize HERG channels in the inactivated state, and (3) block induced by bupivacaine enantiomers is stereoselective.
左旋布比卡因和罗哌卡因分别是N-丁基-和N-丙基-2',6'-哌啶二酰苯胺的纯S(-)对映体，作为布比卡因心脏毒性较小的替代药物而研发。在本研究中，我们分析了左旋布比卡因、罗哌卡因和布比卡因对稳定表达于CHO细胞中的HERG通道的影响。
这三种药物以浓度、时间和状态依赖性方式阻断HERG通道。由20μM布比卡因（52.7±2.0%，n = 15）和罗哌卡因（55.5±2.7%，n = 13）在向-10 mV进行5秒脉冲结束时测得的阻断作用相似（P>0.05），且均低于左旋布比卡因诱导的阻断作用（67.5±4.2%，n = 11）（P<0.05）。
右布比卡因（20μM）的效力低于左旋布比卡因（47.2±5.2%，n = 10）（P<0.05），表明存在对HERG通道的立体选择性阻断。
这三种局部麻醉药诱导的阻断在通道激活范围内表现出陡峭的电压依赖性。在所有情况下，在从失活状态恢复后（I→O）于0 mV测试电位下的最大峰值电流处测得的阻断低于在5秒脉冲结束时（I+O）观察到的阻断。
左旋布比卡因、罗哌卡因和布比卡因加速了HERG失活动力学，减慢了从失活状态的恢复，并使失活曲线向更负的膜电位偏移。在使用快速激活HERG通道的方案后，这三种局部麻醉药均诱导了快速的时间依赖性下降。
所有这些结果表明：（1）这些药物与HERG通道的开放和失活状态结合，（2）它们使HERG通道稳定于失活状态，（3）布比卡因对映体诱导的阻断具有立体选择性。
