Abstract
We have recently identified the molecular determinants of cardiac-specific use dependent block (UDB) by a class 1c antiarrhythmic agent pilsicainide, which are located at transmembrane segments of IVS6. In the present study, the significance of the sites for other antiarrhythmic agents was investigated. The conversion of amino acids for pilsicainide-responsible sites in rat heart sodium channels (Nav.1.5) to those of the corresponding sites in rat brain channels (Nav.1.2) in HEK293 cells, reduced extents of UDB in heart channels by flecainide and quinidine similar to those in brain channels. Interestingly, UDB by lidocaine was also reduced by the conversion above only when short duration (10ms) repetitive pulses were applied. The voltage-dependency of UDB by lidocaine was well correlated with that in the channel activation, suggesting that lidocaine recognizes open-state high affinity sites under this condition. Taking into account the fact that pilsicainide, flecainide and quinidine are all well-known open-channel blockers, these results indicate the possibility that previously identified pilsicainide-responsible sites could be the common significant sites for antiarrhythmic agents in isoform-specific open-channel block of cardiac sodium channels. [Jpn J Physiol 54 Suppl:S125 (2004)]
