Effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels: stereoselective bupivacaine block

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. 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 μ M 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). Dextrobupivacaine (20 μ M ) was less potent (47.2±5.2%, n =10) than levobupivacaine ( P <0.05), indicating stereoselective HERG channel block. 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). 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. 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.British Journal of Pharmacology (2002) 137 , 1269–1279. doi: 10.1038/sj.bjp.0704978