Effects of a quaternary bupivacaine derivative on delayed rectifier K+ currents

1 Block of hKv1.5 channels by R-bupivacaine has been attributed to the inte raction of the charged form of the drug with an intracellular receptor. How ever, bupivacaine is present as a mixture of neutral and charged forms both extra- and intracellularly. 2 We have studied the effects produced by the R(+) enantiomer of a quaterna ry bupivacaine derivative, N-methyl-bupivacaine, (RB(+)1C) on hKv1.5 channe ls stably expressed in Ltk(-) cells using the whole-cell configuration of t he patch-clamp technique. 3 When applied from the intracellular side of the membrane, RB(+)1C induced a time- and voltage-dependent block similar to that induced by R-bupivacai ne. External application of 50 mu M RB(+)1C reduced the current at +60 mV b y 24+/-2% (n=10), but this block displayed neither time- nor voltage-depend ence. 4 External RB(+)1C partially relieved block induced by R-bupivacaine (61+/- 2% vs 56+/-3%, n=4, P<0.05)(-), but it did not relieve block induced by int ernal RB(+)1C. In addition, it did not induce use-dependent block, but when applied in combination with internal RB(+)1C a use-dependent block that in creased with pulse duration was observed. 5 These results indicate that RB(+)1C induces different effects on hKv1.5 c hannels when applied from the intra or the extracellular side of the membra ne, suggesting that the actions of bupivacaine are the resulting of those i nduced on the external and the internal side of hKv1.5 channels.