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Am J Physiol Heart Circ Physiol 274: H477-H487, 1998;
0363-6135/98 $5.00
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Vol. 274, Issue 2, H477-H487, February 1998

Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels

R. Dumaine and G. E. Kirsch

Rammelkamp Center for Research and Department of Physiology and Biophysics, Case Western Reserve University, MetroHealth Campus, Cleveland, Ohio 44109

Inherited long Q-T syndrome is a ventricular arrhythmia associated with delayed repolarization and the risk of sudden death. The chromosome 3-linked form of the disease (LQT3) is associated with mutations in the cardiac Na+ channel (N1325S or R1644H; or deletion of residues 1,505-1,507, Delta KPQ) that increase late inward currents and may cause delayed repolarization. Late currents arise from dispersed reopenings (N1325S and R1644H) or from reopenings combined with prolonged bursts (Delta KPQ). Therefore, we tested whether lidocaine blockade of late current varied among the different LQT3 mutant channels. We found that lidocaine preferentially blocked late over peak current and that the blockade was equally effective in all three channels, expressed in Xenopus oocytes. Lidocaine inhibited both dispersed reopenings and bursting in single channels without affecting mean open times. In the absence of drug, inactivating prepulses inhibited bursting but not dispersed reopenings. We suggest that lidocaine block of late current in LQT3 channels acts via a common mechanism involving stabilization of inactivation. Therefore, blockers that target the inactivated state may be effective therapeutic agents in all three biophysical phenotypes of LQT3.

cardiac arrhythmia; human heart; Romano-Ward syndrome; SCN5A


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